+publisher:"Penn State University" +contributor:("Thomas E Spratt, Committee Member")

You searched for +publisher:"Penn State University" +contributor:("Thomas E Spratt, Committee Member"). Showing records 1 – 21 of 21 total matches.

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Penn State University

1. Ebersole, Brittany Anne. Investigating the role of palmitoylation in the function of the dopamine D2 receptor.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/24760

► The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is crucial for regulation of processes such as mood, reward, and motor control.… (more)

▼ The dopamine D2 receptor (D2R) is a G protein-coupled receptor (GPCR) that is crucial for regulation of processes such as mood, reward, and motor control. Abnormalities in D2R expression and/or neurotransmission are associated with a variety of human disorders, including schizophrenia, Parkinson’s disease, bipolar disorder, depression, and drug abuse. Palmitoylation, the thioester attachment of palmitate to cysteine residues, has become a topic of interest for GPCRs as it has been shown to modulate signaling, trafficking, and stability of these receptors. In this dissertation, an optimized version of bioorthogonal click chemistry (BCC) was developed with the ultimate goal of studying D2R palmitoylation. With this technique, proteins are labeled with the chemical probe 15-hexadecynoic acid (15-HDYA) at sites of palmitoylation. Proteins of interest are then isolated by immunoprecipitation with magnetic beads and analyzed for 15-HDYA incorporation. The utility of this approach was demonstrated by verifying the palmitoylation of the μ-opioid receptor (MOR), a GPCR responsible for mediating the analgesic and addictive properties of most clinically relevant opioid agonist drug. The MOR has been reported to be palmitoylated using two other palmitoylation assays, but not BCC. Additionally, our optimized BCC protocol was able to measure changes in palmitoylation upon overexpression of two palmitoyl acyltransferases (PATs). This was the first demonstration that specific PATs are capable of affecting levels of palmitoylated MOR. While previous experiments in insect cells have shown that the D2R is palmitoylated, nothing was known about the site, function, or enzymes responsible. Here, the palmitoylation of the D2R was analyzed using our modified BCC protocol in a mammalian cell system. Analysis of a series of D2R mutations revealed that palmitoylation of the D2R occurs on the C-terminal cysteine residue (C443) of the polypeptide. Deletion of C443 led to an almost complete absence of D2R palmitoylation and significantly inhibited trafficking of the receptor to the plasma membrane. Rather, the C443 deletion mutant accumulated in the Golgi, indicating that palmitoylation of the D2R is important for cell surface expression of the receptor. Using the full-length D2R as bait in a membrane yeast two-hybrid (MYTH) screen, the palmitoyl acyltransferase (PAT) zDHHC4 was identified as a D2R interacting protein. Co-immunoprecipitation analysis revealed that several other PATs, including zDHHC3 (GODZ) and zDHHC8, also interacted with the D2R and that each of the three PATs was capable of affecting the palmitoylation status of the D2R. Finally, biochemical analysis of the D2R mutants indicates that palmitoylation of the receptor plays a critical role in stability but not the signaling capacity of the D2R.¬ Advisors/Committee Members: Robert G Levenson, Dissertation Advisor/Co-Advisor, Faoud T Ishmael, Committee Member, Patricia Sue Grigson, Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: palmitoylation; dopamine D2 receptor; GPCR; click chemistry; immunoprecipitation; yeast two-hybrid; palmitoyl acyltransferases

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ebersole, B. A. (2015). Investigating the role of palmitoylation in the function of the dopamine D2 receptor. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/24760

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ebersole, Brittany Anne. “Investigating the role of palmitoylation in the function of the dopamine D2 receptor.” 2015. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/24760.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ebersole, Brittany Anne. “Investigating the role of palmitoylation in the function of the dopamine D2 receptor.” 2015. Web. 27 Jan 2021.

Vancouver:

Ebersole BA. Investigating the role of palmitoylation in the function of the dopamine D2 receptor. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/24760.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ebersole BA. Investigating the role of palmitoylation in the function of the dopamine D2 receptor. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/24760

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

2. Lee, Sangmin. Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy.

Degree: 2014, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/22522

► Dopamine D1 receptor full agonists have been efficacious in Parkinson’s disease (PD) animal models and PD patients. SKF-83959 is reported to be a functionally selective… (more)

▼ Dopamine D1 receptor full agonists have been efficacious in Parkinson’s disease (PD) animal models and PD patients. SKF-83959 is reported to be a functionally selective dopamine D1 receptor ligand with high bias for D1-mediated phospholipase C (PLC) versus D1-coupled adenylate cyclase (AC) signaling. The signaling bias of SKF-83959 is commonly accepted and proposed to explain D1-mediated behavioral activity in PD animal models, but there is substantial (although not all unanimous) literature that failed to account for SKF-83959-mediated PLC activation. Thus, we decided to conduct an in-depth pharmacological characterization of SKF-83959. Contrary to common assumptions, SKF-83959 is a partial agonist (not an antagonist) at AC in vitro and ex vivo. In addition, it shows partial agonistic activity for β-arrestin activation. SKF 83959 failed to show D1-mediated PLC signaling in a cellular expression system. We conclude that SKF-83959 is not a highly-biased functionally selective D1 ligand, and that its reported behavioral effects can be explained solely by its partial D1 agonism for canonical signaling pathway(s). Current dopamine D1 receptor full agonists have poor pharmacokinetic properties due to their intrinsic catechol moiety, and it is important to determine how novel non-catechol D1 ligands might be designed. To provide a scientific platform for structure-based drug design, we investigated the molecular interactions of the D1 receptor with several ergolines that have significant D1 activity and oral bioavailability, but not a catechol moiety. I focused on the conserved amino acids of the D1 receptor (T3.37, S5.42, S5.43, S5.46, F6.51, and F6.52) that are known to play a critical role in ligand interactions and/or receptor activation. Mutations to alanine (T3.37A, S5.42A, S5.43A, S5.46A, F6.51A, and F6.52A) on the D1 receptor were basically used to examine the role of the conserved amino acids in ligand interactions. A T3.37A mutation greatly decreased the D1 affinity and efficacy of the ergolines. However, a hydrogen bond-conservative T3.37S mutation markedly restored the loss of D1 affinity and efficacy suggesting the possible role of a hydrogen bond provided by T3.37. Unexpectedly, a S5.42A mutation increased the D1 affinity and efficacy for D1-mediated AC activation suggesting that this mutation may induce a favorable D1 receptor conformation for the ergolines. Although a S5.43A mutation failed to decrease the affinity of the ergolines consistently, a S5.46A mutation significantly decreased the affinity of the ergolines but to a small degree. Both the S5.43A and S5.46A mutations showed no significant effects on D1 efficacy of the ergolines. S5.42A/S5.46A and S5.43A/S5.46A double mutations elicited equal or greater effects than those of the single mutations. An F6.51A mutation dramatically decreased the D1 affinity of the ergolines, and an F6.52A mutation showed smaller, but significant decreases than the F6.51A mutation. The F6.51A mutation greatly decreased the ergoline efficacy for AC activation, but an… Advisors/Committee Members: Richard Bernard Mailman, Dissertation Advisor/Co-Advisor, Richard Bernard Mailman, Committee Chair/Co-Chair, Kent Eugene Vrana, Committee Member, John Ellis, Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: Dopamine D1 receptor; SKF-83959; funtional selectivity; ergolines; rotigotine; structure-based drug design

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Lee, S. (2014). Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/22522

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Lee, Sangmin. “Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy.” 2014. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/22522.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Lee, Sangmin. “Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy.” 2014. Web. 27 Jan 2021.

Vancouver:

Lee S. Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy. [Internet] [Thesis]. Penn State University; 2014. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/22522.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Lee S. Critical signaling and ligand interaction mechanisms of the dopamine D1 receptor: Insight into effective pharmacotherapy. [Thesis]. Penn State University; 2014. Available from: https://submit-etda.libraries.psu.edu/catalog/22522

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

3. Nwokonko, Robert. UNDERSTANDING THE MECHANISM OF UNIMOLECULAR COUPLING BETWEEN STIM AND ORAI.

Degree: 2019, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/17055rmn152

► Store-operated calcium (Ca2+) entry (SOCE) is a ubiquitous signaling mechanism in eukaryotic cells crucial for mediating longer–term Ca2+ signals and restoring endoplasmic/sarcoplasmic (ER/SR) reticulum Ca2+… (more)

▼ Store-operated calcium (Ca2+) entry (SOCE) is a ubiquitous signaling mechanism in eukaryotic cells crucial for mediating longer–term Ca2+ signals and restoring endoplasmic/sarcoplasmic (ER/SR) reticulum Ca2+ after ligand induced depletion. The key operators in SOCE are the Ca2+ selective plasma membrane (PM) Orai1-3 channels and the ER/SR resident, single pass transmembrane Ca2+ sensors STIM1 and STIM2. STIM1 is activated when ER/SR luminal Ca2+ is depleted, inducing it to unfold and bind to Orai1 channels in the PM. Active Orai1 channels create discrete microdomains of high Ca2+ within ER-PM junctions that contain roughly 100-fold greater Ca2+ concentrations than resting cytoplasmic levels. Clustering of Orai channels is critical for generating Ca2+ saturated microdomains, however the mechanism of clustering is not well understood. We have discovered that Orai1 clustering is dependent on the presence of at least two functional C-terminal binding domains of the STIM/Orai Activating Region (SOAR) concatemer dimers. In HEK cells stably expressing Orai1 labelled with a repetitive histidine tag, Orai1-His cells, and transiently expressing wildtype SOAR-SOAR (S-S) concatemers, we observe an increase in SOAR-Orai1 colocalization, visualized as the formation of puncta in the plasma membrane. When one subunit within a SOAR concatemer has the phenylalanine-394 residue mutated to histidine (F394H) in either SH-S or S-SH configurations, a residue critical for high-affinity C-terminal binding to Orai1, there is a dramatic decrease in puncta. Similar to the F394H mutation, the STIM2 splice variant STIM2.1 has an additional 8 amino acid insertion within the C-terminal binding domain of the SOAR2 region, and concatemerized S-S2.1 peptides are also unable to cluster Orai1 channels. We also observe that linking a large fluorescent protein, CFP, to the C-terminus of Orai1 can sterically hinder clustering. HEK Orai1-CFP stable cells do not form puncta, regardless of the presence of two functional C-terminal binding domains on SOAR concatemers. There is also a functional difference in the calcium current passing through Orai channels (ICRAC) magnitude in HEK Orai1-His cells that is dependent on the presence of two functional SOAR subunits. Intriguingly, this dependence is absent in sterically hindered cells. Along with these biophysical studies, much has been done to study the role of Orai1 clustering in maintaining intracellular Ca2+ homeostasis. We find that the coexpression of full-length STIM1 and STIM2.1 dramatically impacts the ability for cells to maintain muscarinic agonist-induced regenerative Ca2+ oscillations in cells. My data suggests that this diminishment in oscillations is driven by decreased ER Ca2+ refilling in cells that are unable to cluster Orai1. We also observe that the ability for different NFAT isoforms to translocate into the nucleus after SOCE is altered by the ability for Orai1 to cluster or not cluster. In summary, my thesis research demonstrates that clustering of Orai1 channels is dependent on the presence… Advisors/Committee Members: Donald Leon Gill, Dissertation Advisor/Co-Advisor, Mohamed Trebak, Committee Chair/Co-Chair, Thomas E Spratt, Committee Member, Blaise Peterson, Committee Member, Jong Kak Yun, Outside Member, Ralph Lauren Keil, Program Head/Chair.

Subjects/Keywords: Store operated calcium channels; Electrophysiology; Membrane proteins; Orai calcium channel; Endoplasmic reticulum; Calcium signalling

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nwokonko, R. (2019). UNDERSTANDING THE MECHANISM OF UNIMOLECULAR COUPLING BETWEEN STIM AND ORAI. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/17055rmn152

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nwokonko, Robert. “UNDERSTANDING THE MECHANISM OF UNIMOLECULAR COUPLING BETWEEN STIM AND ORAI.” 2019. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/17055rmn152.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nwokonko, Robert. “UNDERSTANDING THE MECHANISM OF UNIMOLECULAR COUPLING BETWEEN STIM AND ORAI.” 2019. Web. 27 Jan 2021.

Vancouver:

Nwokonko R. UNDERSTANDING THE MECHANISM OF UNIMOLECULAR COUPLING BETWEEN STIM AND ORAI. [Internet] [Thesis]. Penn State University; 2019. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/17055rmn152.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Nwokonko R. UNDERSTANDING THE MECHANISM OF UNIMOLECULAR COUPLING BETWEEN STIM AND ORAI. [Thesis]. Penn State University; 2019. Available from: https://submit-etda.libraries.psu.edu/catalog/17055rmn152

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

4. Bushey, Ryan Taylor. Role of the Uridine Diphosphate Glucuronosyltransferase 2a Family in Tobacco Carcinogen Metabolism.

Degree: 2012, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/15808

► Tobacco use is considered the most preventable cause of death in the world today, with tobacco-related cancers causing millions of deaths annually. Environmental and genetic… (more)

▼ Tobacco use is considered the most preventable cause of death in the world today, with tobacco-related cancers causing millions of deaths annually. Environmental and genetic factors are known to impact cancer susceptibility, and using environmental exposure and/or genetic information to identify a subset of individuals at high-risk for developing tobacco-related cancers has the potential to save many lives. Inter-individual differences in enzymes that activate and metabolize carcinogens are thought to influence cancer risk. UDP-glucuronosyltransferases (UGTs) are phase II detoxifying enzymes that play a critical role in the metabolism of endogenous and exogenous compounds, including multiple classes of tobacco carcinogens. The effects of coding and non-coding SNPs on UGT activity have been analyzed for many UGT isoforms, and multiple UGT variants have been determined to be significantly associated with cancer risk. The entire UGT2A family has been neglected in prior research studies, with UGT2A tissue expression and enzyme activities relatively unknown. With recent reports suggesting UGT2A1 expression in the lung and trachea and UGT2A1 glucuronidation activity against simple polycyclic aromatic hydrocarbon (PAH) substrates, the overall hypothesis of this research project was that UGT2A1 detoxifies PAH carcinogens in target organs for tobacco carcinogenesis. Due to the sequence homology between all UGT2A enzymes, and with little information reported on UGT2A2 or UGT2A3, we also hypothesized that UGT2A2 and UGT2A3 enzymes are involved in extra-hepatic tobacco carcinogen metabolism. An initial set of experiments was completed to characterize the role of UGT2A1 in tobacco carcinogen metabolism. Quantitative real-time PCR showed highest relative UGT2A1 expression in the lung, followed by trachea > tonsil > larynx > colon. Significant UGT2A1 glucuronidation activity was observed against a variety of PAHs, including the proximate carcinogens benzo(a)pyrene(B(a)P)-7,8-diol, dibenzo(a,l)pyrene-11,12-diol, and 5-methylchrysene-1,2-diol. No UGT2A1 glucuronidation activity was observed against additional classes of tobacco carcinogens, including tobacco specific nitrosamines or heterocyclic amines. In vitro experiments suggested that UGT2A1 over-expression in a HEK293 cell system prevents B(a)P-mediated cytotoxicity and covalent binding. These data suggested that UGT2A1 is an important detoxification enzyme in the metabolism of PAHs within aerodigestive and respiratory tract tissues. The next set of experiments focused on characterizing two prevalent UGT2A1 non-synonymous coding SNPs, the UGT2A175Lys and UGT2A1308Arg variants. The UGT2A175Arg variant exhibited a significant (p<0.05) ~25% decrease in glucuronidation activity (Vmax/KM) against all PAH substrates examined compared to wild-type UGT2A175Lys activity, while no detectable glucuronidation activity was observed for the UGT2A1308Arg variant against all substrates examined. Results from a lung cancer case-control study showed the inactive UGT2A1308Arg… Advisors/Committee Members: Philip Lazarus, Dissertation Advisor/Co-Advisor, Shantu G Amin, Committee Member, John Ellis, Committee Member, Melvin Lee Billingsley, Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: UDP-glucuronosyltransferase; tobacco carcinogen metabolism; single nucleotide polymorphism; alternate splicing; UGT regulation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bushey, R. T. (2012). Role of the Uridine Diphosphate Glucuronosyltransferase 2a Family in Tobacco Carcinogen Metabolism. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/15808

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Bushey, Ryan Taylor. “Role of the Uridine Diphosphate Glucuronosyltransferase 2a Family in Tobacco Carcinogen Metabolism.” 2012. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/15808.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Bushey, Ryan Taylor. “Role of the Uridine Diphosphate Glucuronosyltransferase 2a Family in Tobacco Carcinogen Metabolism.” 2012. Web. 27 Jan 2021.

Vancouver:

Bushey RT. Role of the Uridine Diphosphate Glucuronosyltransferase 2a Family in Tobacco Carcinogen Metabolism. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/15808.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Bushey RT. Role of the Uridine Diphosphate Glucuronosyltransferase 2a Family in Tobacco Carcinogen Metabolism. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/15808

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

5. Titchenell, Paul Michael. Targeting Atypical Protein Kinase C Isoforms for the Prevention of Blood-Retinal Barrier Dysfunction in Ophthalmic Disease.

Degree: 2012, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/16383

► Blood-Retinal Barrier (BRB) dysfunction and subsequent macular edema (ME) are hallmarks of several ocular diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), uveitis, and… (more)

▼ Blood-Retinal Barrier (BRB) dysfunction and subsequent macular edema (ME) are hallmarks of several ocular diseases including diabetic retinopathy (DR), age-related macular degeneration (AMD), uveitis, and retinal vein occlusions (RVO). Vascular endothelial growth factor (VEGF) is a main pathological driver of the vascular permeability and BRB abnormalities observed in these insults. Importantly, agents targeting VEGF are robust medical therapies that have revolutionized eye care. However, only 35% of patients improve vision while 60% have further loss vision loss prevented when treated with anti-VEGF therapies suggesting alternative factors are also able to induce BRB dysfunction. Tumor necrosis factor (TNF) contributes to retinal inflammation and is a candidate to mediate some of the deleterious effects observed in these diseases. Therefore, elucidating the downstream commonalities of VEGF and TNF signaling may provide an ideal point of therapeutic intervention. This dissertation tests the hypothesis that the atypical protein kinase C (aPKC) isoforms represent a common permeabilizing signaling node downstream of VEGF and TNF. Previously data from our laboratory defines an essential role for aPKC in TNF-induced retinal endothelial permeability. Building upon this observation, the contribution of aPKC to VEGF-induced retinal endothelial permeability was assessed. Here, VEGF treatment activated aPKC in both primary retinal endothelial cells and in the rodent retina. Furthermore, pharmacological and genetic manipulation of aPKC demonstrated that aPKC not only contributed to VEGF-induced permeability but also was sufficient to increase endothelial permeability. Novel small molecule inhibitors of aPKC were identified and were shown to prevent VEGF-induced retinal permeability in primary culture and in the rodent retina. Data in chapter 3 of the dissertation provides evidence that aPKC isoforms mediate VEGF-induced permeability and identifies novel small molecules inhibitors of aPKC isoforms and are effective anti- permeabilizing agents that warrant further investigation. Further characterization of the novel small molecule aPKC inhibitors was performed to define the structural requirements necessary for inhibitory activity. Detailed structure-activity relationships (SAR) were performed which delineated a novel pharmacophore required for inhibitory activity in two aPKC-dependent cell based assays that measure inflammation and vascular permeability. Data in chapter 4 provides the structural framework necessary for future medicinal chemistry efforts to solidify this chemotype as a clinically efficacious compound and identified a lead compound for further in vivo study (aPKC-I-diMeO). The contribution of aPKC isoforms to VEGF and TNF-induced BRB dysfunction and retinal edema was assessed using these newly identified small molecule inhibitors of aPKC. Importantly, both terminal and non-terminal assays to measure the extent VEGF/TNF-induced BRB dysfunction and retinal edema were utilized. Here, a nanomolar potent aPKC… Advisors/Committee Members: Charles H Lang, Dissertation Advisor/Co-Advisor, Charles H Lang, Committee Chair/Co-Chair, Thomas E Spratt, Committee Member, David Antonetti, Special Member, Yuguang Shi, Committee Member, Christopher Martin Yengo, Committee Member.

Subjects/Keywords: vegf; drug discovery; PKC; blood-retinal barrier; vascular permeability; macular edema; phosphoproteomics; kinase inhibitor; TNF

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Titchenell, P. M. (2012). Targeting Atypical Protein Kinase C Isoforms for the Prevention of Blood-Retinal Barrier Dysfunction in Ophthalmic Disease. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/16383

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Titchenell, Paul Michael. “Targeting Atypical Protein Kinase C Isoforms for the Prevention of Blood-Retinal Barrier Dysfunction in Ophthalmic Disease.” 2012. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/16383.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Titchenell, Paul Michael. “Targeting Atypical Protein Kinase C Isoforms for the Prevention of Blood-Retinal Barrier Dysfunction in Ophthalmic Disease.” 2012. Web. 27 Jan 2021.

Vancouver:

Titchenell PM. Targeting Atypical Protein Kinase C Isoforms for the Prevention of Blood-Retinal Barrier Dysfunction in Ophthalmic Disease. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/16383.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Titchenell PM. Targeting Atypical Protein Kinase C Isoforms for the Prevention of Blood-Retinal Barrier Dysfunction in Ophthalmic Disease. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/16383

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

6. Olson, Thomas Lynn. Identification of Somatic Mutations in LGL Leukemia through Whole Genome Sequencing and Correlation of STAT3 Y640F Mutation with Treatment Response to Methotrexate.

Degree: 2013, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/18951

► The rare disorder, large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of cytotoxic cells. Normal LGL are critical to the removal of… (more)

▼ The rare disorder, large granular lymphocyte (LGL) leukemia is characterized by a clonal expansion of cytotoxic cells. Normal LGL are critical to the removal of virally-infected or tumor cells from the body. These cells normally expand when there is an immune challenge and then rapidly undergo apoptosis when the antigen is cleared, but leukemic LGLs are resistant to apoptosis. Serological evidence indicates that LGL leukemia may be driven by chronic infection of an unknown retrovirus. Patients with LGL leukemia frequently experience autoimmune conditions such as rheumatoid arthritis and also experience cytopenias requiring medical intervention. The study of LGL leukemia is therefore important both from a patient standpoint and as a model of normal LGL. We have recently discovered and characterized multiple somatic mutations in exon 20 and 21 of STAT3 from exome sequencing of an LGL leukemia patient and confirmed this mutation to be present in both Natural Killer and T cell leukemias. A small percentage was also found to have mutations in STAT5B, with some associated with an aggressive phenotype. Concurrently, we have undertaken whole genome sequencing to determine what other mutations may contribute to LGL leukemia and to expand our knowledge of STAT3 activation. Given the antigen driven nature of LGL leukemia, it is unclear what mutations are necessary for their lack of apoptosis and whether these will resemble those seen in other leukemias. The current treatment of choice for LGL leukemia is immunosuppressive methotrexate. Firstly, we present the first large prospective trial of immunosuppressive therapy in LGL leukemia. In this trial we identify a correlation between a particular Y640F mutation in STAT3 and a favorable response to first line treatment with methotrexate. We measure and report 27 serum cytokines collected for this trial, none of which were a priori predictive of treatment response. Through microarray analysis we identified a gene expression signature indicative of response. Interestingly, this gene signature does not appear to be driven by STAT3 mutation in all samples. We propose that there are other methods of STAT activation in these samples and advance a model of how the Y640F mutation enforces response. Secondly, we collaboratively sequenced 6 paired, leukemic/saliva genomes from three LGL patients at a high rate of coverage. Two patient genomes contain a direct STAT3 mutation. In the third patient we observe a mutation in the 3' UTR of the IL6R that could activate JAK-STAT signaling if it is shown to regulate translation. Mutations in the histone modifiers, MLL2, MLL3 and NCOR1 are supported in the sequence reads of all three genomes. Alterations in this pathway would be a new observation for LGL leukemia. We identify and catalog numerous other mutations which may give insight into LGL biology that could allow us to better understand how symptoms arise and differ between patients and why current treatments may fail. Lastly, we present data identifying important… Advisors/Committee Members: "Thomas P Loughran, Jr", Dissertation Advisor/Co-Advisor, Rosalyn Bryson Irby, Committee Chair/Co-Chair, Thomas E Spratt, Committee Member, Richard James Courtney, Committee Member, Bruce A Stanley, Special Member.

Subjects/Keywords: large granular lymphocytes; leukemia; STAT3; TBET; genomics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Olson, T. L. (2013). Identification of Somatic Mutations in LGL Leukemia through Whole Genome Sequencing and Correlation of STAT3 Y640F Mutation with Treatment Response to Methotrexate. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/18951

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Olson, Thomas Lynn. “Identification of Somatic Mutations in LGL Leukemia through Whole Genome Sequencing and Correlation of STAT3 Y640F Mutation with Treatment Response to Methotrexate.” 2013. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/18951.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Olson TL. Identification of Somatic Mutations in LGL Leukemia through Whole Genome Sequencing and Correlation of STAT3 Y640F Mutation with Treatment Response to Methotrexate. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/18951.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Olson TL. Identification of Somatic Mutations in LGL Leukemia through Whole Genome Sequencing and Correlation of STAT3 Y640F Mutation with Treatment Response to Methotrexate. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/18951

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

7. Zhang, Shang-min. Oral Cancer Induced by The Tobacco Carcinogen Dibenzo[a,l]pyrene in Mice.

Degree: 2013, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/18930

► Oral cancer is the most common type of head and neck cancer, which is the sixth most common cancer worldwide. More than 90% of oral… (more)

▼ Oral cancer is the most common type of head and neck cancer, which is the sixth most common cancer worldwide. More than 90% of oral cancers are a type called oral squamous cell carcinoma (OSCC). Tobacco use is the most important risk factor. Chronic and/or heavy use of alcohol is another major risk factor. Early detection and prevention of oral cancer is very pivotal. Progress in the prevention and control of oral cancer has been hampered by the lack of appropriate animal models that could reflect human exposure. Therefore, experimental animal models that can accurately represent the cellular and molecular changes associated with the initiation and progression of human oral cancer are of crucial importance to better understand the mechanisms of oral carcinogenesis and to identify novel chemopreventive, as well as chemotherapeutic agents. We recently developed a novel mouse model to study oral carcinogenesis. We showed for the first time that direct application of DB[a,l]P into the oral cavity, induced SCC in oral tissues; (±)-anti-DB[a,l]PDE-diol epoxide, the ultimate metabolite of DB[a,l]P, is a remarkably potent carcinogen in the oral cavity (both oral tissues and tongue). The mechanisms that can account for oral cancer-induced by this tobacco carcinogen are the focus of this dissertation. Our working hypothesis is that both genetic and epigenetic alterations induced by DB[a,l]P can contribute to the development of oral cancer. To test our hypothesis, we focused initially on assessing the effect of this carcinogen on genetic alterations. We have developed a new stable isotope dilution HPLC-MS/MS method to identify and quantify DB[a,l]PDE-dA and -dG adducts in oral tissue of mice. Our method is sensitive enough to detect DNA adducts in vivo. We detected (-)-anti-cis- and (-)-anti-trans-DB[a,l]PDE-N6-dA and (-)-anti-cis- and (-)-anti-trans-DB[a,l]PDE-N2-dG adducts in oral and tongue tissues of mice treated with DB[a,l]P; the results indicate that the levels of dA adducts are significantly higher than dG adducts and that DB[a,l]P is predominantly metabolized to (-)-anti-DB[a,l]PDE. Using immunohistochemistry (IHC), we have shown over-expression of p53 and COX-2 protein in OSCC and dysplastic tissues induced by DB[a,l]P and DB[a,l]PDE in mice. P53 protein overexpression detected by IHC may result from p53 gene mutation or exposure to genotoxic stress. To determine whether p53 over-expression is, in part, due to p53 mutations, Exons 5 to 8 of p53 from representative tumor tissues, were analyzed by polymerase chain reaction single-strand conformation polymorphisms (PCR-SSCP) and direct sequencing. G:C→T:A transversion was detected in Exon 5, leading to mutation of codon 155 Arg to Leu; A:T → T:A transversion was detected in Exon 7, resulting in mutation of codon 232 Lys to stop codon. To further test our hypothesis, we examined the epigenetic effect of DB[a,l]P exposure. Methylation specific PCR and bisulfite sequencing were used to examine methylation alteration of p16 and RAR-β promoters. Promoter… Advisors/Committee Members: Karam E El Bayoumy, Dissertation Advisor/Co-Advisor, Kristin Ann Eckert, Committee Member, John Peter Richie Jr., Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: Oral Cancer; Tobacco Carcinogen; DB[a; l]P; DNA adducts; LC-MS/MS; p53 mutations; epigenetics; alcohol; chemoprevention

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Zhang, S. (2013). Oral Cancer Induced by The Tobacco Carcinogen Dibenzo[a,l]pyrene in Mice. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/18930

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Zhang, Shang-min. “Oral Cancer Induced by The Tobacco Carcinogen Dibenzo[a,l]pyrene in Mice.” 2013. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/18930.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Zhang, Shang-min. “Oral Cancer Induced by The Tobacco Carcinogen Dibenzo[a,l]pyrene in Mice.” 2013. Web. 27 Jan 2021.

Vancouver:

Zhang S. Oral Cancer Induced by The Tobacco Carcinogen Dibenzo[a,l]pyrene in Mice. [Internet] [Thesis]. Penn State University; 2013. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/18930.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Zhang S. Oral Cancer Induced by The Tobacco Carcinogen Dibenzo[a,l]pyrene in Mice. [Thesis]. Penn State University; 2013. Available from: https://submit-etda.libraries.psu.edu/catalog/18930

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

8. Liu, Ying. Mechanistic studies on Bif-1 function in obesity and Atg9 trafficking.

Degree: 2016, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/13447yxl240

► Autophagy, the catabolic process whereby intracellular components are degraded by the lysosome, is long recognized for its roles in maintaining cellular energetic balance by breaking… (more)

▼ Autophagy, the catabolic process whereby intracellular components are degraded by the lysosome, is long recognized for its roles in maintaining cellular energetic balance by breaking down dysfunctional proteins and recycling the amino acids. Adding to this classic view, recent studies have found that autophagy also directly impacts energetics by degrading lipids. This process, referred to as lipophagy, serves to prevent excessive fat accumulation in multiple tissues such as the liver and skeletal muscle, and modulates the hormone production in hypothalamus to affect food intake. The molecular mechanisms of lipophagy, particularly those related to the biogenesis of autophagosome to sequester the substrates, are unclear due to poor understanding of the responsible molecular interactions. Moreover, in the largest lipid storage organ - adipose tissue – it is unknown whether autophagy plays a role in fat degradation. It has been established that autophagy is essential for early development including embryonic adipogenesis, but it is not known if impairment of this catabolic process in an individual with mature adipose tissue leads to obesity. Bif-1 is a previously identified positive regulator of autophagy that interacts with UVRAG, and modulates Atg9 trafficking to promote the formation of autophagosomes. The current study identified Bif-1 as a novel regulator in lipid catabolism that will prevent the development of obesity and insulin resistance upon aging or dietary challenge. My data show that Bif-1 deficiency promotes the expansion of adipose tissue mass without altering food intake or physical activities. Although Bif-1 is dispensable for adipose tissue development, its deficiency reduces the rate of adipose tissue lipolysis, lowers the degradation of autophagy adaptor and substrate p62, and results in adipocyte hypertrophy upon aging. This function of Bif-1 in lipid turnover is not limited to adipose tissue since lipid droplet clearance is also attenuated by Bif-1 loss in the liver of mice that were starved and re-fed. Interestingly, obesity induced by a high fat-diet or Bif-1 deficiency down-regulates the protein levels of Atg9 and a lysosomal protein Lamp1 in the adipose tissue. Together, my research discovered a new role for Bif-1 in regulating lipid metabolism likely via lipophagy. Many questions remain, for example, does Bif-1-mediated lipid degradation depend on Atg9, and what other potential interactors of the Atg9-Bif-1 complex promote the biogenesis of autophagosomes? In order to address this question, we performed an Atg9 interactome profiling using inducible protein crosslinking coupled with affinity purification and proteomics. This identified VCP/p97 as a novel interactor with Atg9. Moreover, genetic knockdown of VCP in cells appears to disrupt autophagosome maturation. Although further studies are needed to precisely dissect the function of VCP in the autophagy machinery, I propose a potential role for VCP in the retrieval of autophagy proteins from the autophagosome. In summary, my research has… Advisors/Committee Members: Hong-Gang Wang, Dissertation Advisor/Co-Advisor, Hong-Gang Wang, Committee Chair/Co-Chair, Richard Bernard Mailman, Committee Member, Thomas E Spratt, Committee Member, Yoshinori Takahashi, Outside Member, Yuguang (Roger) Shi, Outside Member.

Subjects/Keywords: Bif-1; Atg9; obesity; autophagy; lipid metabolism; lipophagy

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Liu, Y. (2016). Mechanistic studies on Bif-1 function in obesity and Atg9 trafficking. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13447yxl240

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Liu, Ying. “Mechanistic studies on Bif-1 function in obesity and Atg9 trafficking.” 2016. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/13447yxl240.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Liu, Ying. “Mechanistic studies on Bif-1 function in obesity and Atg9 trafficking.” 2016. Web. 27 Jan 2021.

Vancouver:

Liu Y. Mechanistic studies on Bif-1 function in obesity and Atg9 trafficking. [Internet] [Thesis]. Penn State University; 2016. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/13447yxl240.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Liu Y. Mechanistic studies on Bif-1 function in obesity and Atg9 trafficking. [Thesis]. Penn State University; 2016. Available from: https://submit-etda.libraries.psu.edu/catalog/13447yxl240

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

9. Tash, Brian Richard. BIOPHYSICAL CHARACTERIZATION OF TIGHT JUNCTION PROTEINS .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11628

► The tight junction (TJ) is a complex of transmembrane, peripheral membrane and signaling proteins that together form a barrier to the flow of solute and… (more)

▼ The tight junction (TJ) is a complex of transmembrane, peripheral membrane and signaling proteins that together form a barrier to the flow of solute and molecules through the paracellular space in polarized epithelial cells. The major transmembrane proteins of the TJ are occludin (bicellular-TJ) and tricellulin (tricellular-TJ), which regulate TJ barrier properties, and the claudins, which form the TJ barrier. These proteins are anchored to the actin cytoskeleton through the membrane peripheral scaffolding protein, ZO1. Specifically, the coiled-coil domain of occludin (occCC) located at the distal end of their intracellular C-terminal tail, interacts with the SH3-GuK domains of ZO1. The role of the occludin-ZO1 interaction in the regulation of TJ barrier properties has been studied extensively. Loss of this interaction correlates with reduced barrier properties of the TJ. Studies have supported a role for multi-site phosphorylation of occludin in regulating complex formation. It has been shown that phosphorylation on Ser490, within occCC, is involved in regulation of tight junction barrier properties by controlling binding to ZO1, occludin ubiquitination, and trafficking into early endosomes. However, the molecular mechanisms underlying the occludin-ZO1 interaction are unknown, and how Ser490 phosphorylation regulates TJ properties is obscure. A second site, Ser471, located in the negatively charged head of occCC, was also found to be phosphorylated in vivo, but its role is also unclear. The related, but distinct, tricellulin-ZO1 interaction is less well characterized and its phosphorylation state unclear. The hypothesis of this thesis is that phosphorylation of specific sites on occCC regulates its interaction with ZO1, thereby potentially regulating bicellular TJ complex formation and by extension, the equivalent region in tricellulin and tricellular TJs. To test this, experiments were designed to structurally characterize the interactions between the coiled-coil domains of either occludin or tricellulin, respectively, with the PDZ3-SH3-GuK (PSG) domains of ZO1. A range of biophysical techniques were used to characterize the PSG domains of ZO1 and occCC individually and in a complex, including circular dichroism (CD), hydrogen-deuterium exchange mass spectroscopy (HDEX) , multi-angle laser light scattering (MALLS) and nuclear magnetic resonance (NMR). The functional state of the protein was assessed using nuclear magnetic resonance (NMR) chemical shift perturbation assays. These studies revealed that binding of occCC to the GuK domain of ZO1 altered the structure of its PDZ3 domain, suggesting a mode of communication between the various protein binding sites within ZO1. To gain an understanding of the molecular mechanisms underlying the occludin-ZO1 protein complex and the location of Ser490 and Ser471 in this complex, various biophysical tools were used to characterize structurally occCC in a complex with the PSG domains of ZO1. Initially, small angle X-ray scattering (SAXS) was used to… Advisors/Committee Members: John Michael Flanagan Jr., Dissertation Advisor/Co-Advisor, John Michael Flanagan Jr., Committee Chair/Co-Chair, David Antonetti, Committee Member, Ira Joseph Ropson, Committee Member, Thomas E Spratt, Committee Member, Anthony Edward Pegg, Committee Member.

Subjects/Keywords: ZO-1; tight junctions; occludin

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tash, B. R. (2011). BIOPHYSICAL CHARACTERIZATION OF TIGHT JUNCTION PROTEINS . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11628

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Tash, Brian Richard. “BIOPHYSICAL CHARACTERIZATION OF TIGHT JUNCTION PROTEINS .” 2011. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/11628.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Tash, Brian Richard. “BIOPHYSICAL CHARACTERIZATION OF TIGHT JUNCTION PROTEINS .” 2011. Web. 27 Jan 2021.

Vancouver:

Tash BR. BIOPHYSICAL CHARACTERIZATION OF TIGHT JUNCTION PROTEINS . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/11628.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Tash BR. BIOPHYSICAL CHARACTERIZATION OF TIGHT JUNCTION PROTEINS . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/11628

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

10. Duncan, Kimberly JoAnne. Molecular Mechanisms of Growth Inhibition by the Chymotrypsin-like Serine Protease Inhibitor, AAPFcmk .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11419

► Cervical cancer is the second most prevalent cancer in woman worldwide (Kamangar et al., 2006). Infection with one of the 15 known high-risk human papillomavirus… (more)

▼ Cervical cancer is the second most prevalent cancer in woman worldwide (Kamangar et al., 2006). Infection with one of the 15 known high-risk human papillomavirus (HPV) types is etiologically linked to 95% of cervical cancer (zur Hausen, 1996). Multiple studies have also causally linked oncogenic HPV infection to 25% of head and neck squamous cell carcinomas (HNSCC). Recently, preventative virus-like particle (VLP) vaccines against HPV-16 and HPV-18, two of the most common high-risk HPVs (Munoz et al., 2003), have been approved. However, the participation of HPV in the development of multiple types of cancer, the prevalence of infected women in less developed countries and the current negative reproductive consequences of treatment makes finding novel and affordable therapies critical to treating established HPV infections. AAPFcmk is a chymotrypsin-like serine protease inhibitor that has been shown to inhibit the growth of organotypic raft cultures containing cells with high-risk HPV types, with no effect observed on uninfected keratinocytes (Drubin et al. 2006). Since many proteases have been shown to be overexpressed in cancer, protease inhibitors have become candidates for use in cancer therapeutics (Turk, 2006). The Bowman-Birk serine protease inhibitor (which has mainly chymotrypsin-specific activity), has been in clinical trials for its anticarcinogenic activity against oral cancer. AAPFcmk has not only shown the ability to inhibit the growth of high-risk HPV cells but also has demonstrated anticarcinogenic activity in a number of model systems and is relatively selective for a nuclear protease (Clawson et al., 1992b). Investigation into potential binding targets of AAPFcmk found multiple targets which are not proteases including ATP-dependent helicases (Dhamne et al., 2006). AAPFcmk was shown to inhibit the ATP-dependent helicase activity of the SV40 Large T-antigen in vitro. However, the molecular mechanisms of inhibition induced in HPV-infected cervical cancer cells by AAPFcmk have not yet been determined. Understanding how AAPFcmk inhibits the growth of human cervical cancer cells at a molecular level could identify possible treatment options, including its prospect as a topical therapeutic, and applications in combination therapies. We hypothesized that AAPFcmk would arrest the growth of cervical cancer cell lines and cell lines immortalized or transformed by the integration of the SV40 and HPV small DNA tumor viruses through inhibition of the cell cycle based on previous studies (Clawson et al., 1995) (Drubin et al., 2006). We also hypothesized that AAPFcmk growth arrests cell lines infected by the small DNA tumor viruses, SV40 and HPV-16, by blocking the ability of the SV40 Large T-antigen (SV40 LTag), HPV-16 E6 and/or HPV-16 E7 oncoproteins from interacting with the tumor suppressor proteins, p53 and pRb. Both the SV40 LTag and HPV-16 E6 protein functionally inactivate p53 and the downstream cyclin-dependent kinase inhibitor p21, however the mechanism of p53 inactivation is… Advisors/Committee Members: Kristin Eckert, Dissertation Advisor/Co-Advisor, Kristin Ann Eckert, Committee Chair/Co-Chair, Gary Alan Clawson, Committee Chair/Co-Chair, Neil David Christensen, Committee Member, Thomas E Spratt, Committee Member, John Peter Richie Jr., Committee Member.

Subjects/Keywords: HPV; AAPFcmk; cervical cancer; serine protease inhibitor

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Duncan, K. J. (2011). Molecular Mechanisms of Growth Inhibition by the Chymotrypsin-like Serine Protease Inhibitor, AAPFcmk . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11419

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Duncan, Kimberly JoAnne. “Molecular Mechanisms of Growth Inhibition by the Chymotrypsin-like Serine Protease Inhibitor, AAPFcmk .” 2011. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/11419.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Duncan, Kimberly JoAnne. “Molecular Mechanisms of Growth Inhibition by the Chymotrypsin-like Serine Protease Inhibitor, AAPFcmk .” 2011. Web. 27 Jan 2021.

Vancouver:

Duncan KJ. Molecular Mechanisms of Growth Inhibition by the Chymotrypsin-like Serine Protease Inhibitor, AAPFcmk . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/11419.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Duncan KJ. Molecular Mechanisms of Growth Inhibition by the Chymotrypsin-like Serine Protease Inhibitor, AAPFcmk . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/11419

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

11. Pang, Min. Down-regulation of H-ferritin in Glioma.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/26714

► Human gliomas are notorious for their resistance to conventional therapy and high recurrence, thus there is a need for improvement in therapeutic strategies. Human glioma… (more)

▼ Human gliomas are notorious for their resistance to conventional therapy and high recurrence, thus there is a need for improvement in therapeutic strategies. Human glioma cells have modified iron metabolism, as well as an elevated level of the iron storage protein, ferritin. Previously it has been shown that the down-regulation of one of the ferritin subunits, H-ferritin, increases sensitivity of human glioma cells to the chemotherapeutic agent BCNU. In this dissertation, I tested the hypothesis that H-ferritin down-regulation increases radiosensitivity in glioma cells, explored the mechanism for the sensitization effect, and investigated the potential of targeting H-ferritin as an adjuvant therapy in glioma treatment. In the first set of studies, the down-regulation of H-ferritin was achieved by liposomal transfection in human glioma cell line U251. Although H-ferritin down-regulation alone did not affect cell proliferation, the combination of down-regulation and high doses of radiation led to significantly enhanced toxicity. To elucidate the mechanism underlying the increased sensitivity I used a cell culture approach. The in vitro assay revealed that H-ferritin down-regulation was accompanied with disruption in iron metabolism, increased oxidative stress, and decreased stability of hypoxia-inducible factor (HIF)-2α. Furthermore, in the presence of ionizing radiation, down-regulation of H-ferritin was associated with decreased level of the phosphorylated form of ATM kinase. These effects are consistent with the radiosensitization effect observed. In a second series of studies, the effect of H-ferritin down-regulation was evaluated in glioma stem cells (GSCs), a subpopulation of glioma cells that are preferentially resistant to therapies and are capable of self-renewal. Different from the cell line study, the down-regulation of H-ferritin resulted in an inhibition in GSCs proliferation. An increased level of PARP cleavage was observed, suggesting that induction of apoptosis may be the cause of this inhibition in proliferation. Although no significant oxidation damage was observed in GSCs with H-ferritin siRNA transfection, these cells demonstrated enhanced radiosensitivity, suggesting a different mechanism may be involved in GSCs radiosensitization. Moreover, in vivo study showed that tumors formed by GSCs can be sensitized to chemotherapeutic agent by H-ferritin siRNA transfection. Finally, I explored an active targeting strategy by developing the liposomes to enhance the transfection efficiency and specificity in vivo. Maleimide lipids were incorporated in the formulation of liposomes for IL-13 ligand conjugation for the purpose of targeting IL-13 receptor, a specific surface marker for human glioma. The characterization of the maleimide liposomes confirmed their quality. Both DNA complexation and ligand conjugation of the liposomes were demonstrated by biochemical analysis. Although the original formulation we developed was not efficient at gene delivery, the modified formulation with lower maleimide content… Advisors/Committee Members: James Robert Connor, Dissertation Advisor/Co-Advisor, James Robert Connor, Committee Chair/Co-Chair, Thomas E Spratt, Committee Member, Rosalyn Bryson Irby, Committee Member, Richard Bernard Mailman, Special Member.

Subjects/Keywords: Glioma; radiosensitization; H-ferritin; iron metabolism; glioma stem cells; liposomes

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Pang, M. (2015). Down-regulation of H-ferritin in Glioma. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/26714

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Pang, Min. “Down-regulation of H-ferritin in Glioma.” 2015. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/26714.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Pang, Min. “Down-regulation of H-ferritin in Glioma.” 2015. Web. 27 Jan 2021.

Vancouver:

Pang M. Down-regulation of H-ferritin in Glioma. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/26714.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Pang M. Down-regulation of H-ferritin in Glioma. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/26714

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

12. Skibinski, Christine G. preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/26720

► As discussed in Chapter 1, Breast cancer is the second leading cause of cancer death in women in the United States, with about 2 million… (more)

▼ As discussed in Chapter 1, Breast cancer is the second leading cause of cancer death in women in the United States, with about 2 million women at high risk for developing the disease. A current strategy, approved by the FDA, for breast cancer prevention is the daily administration of selective estrogen receptor modulators(SERMS), tamoxifen and raloxifene. These SERMS have proven to be effective at reducing breast cancer incidence in women that are at high risk by 50% and 38%, respectively. However, these agents are poorly accepted as oral chemopreventives even by women at high risk for breast cancer because of concerns of side effects which include thromboembolic events and an increase in endometrial cancers. Furthermore, both agents are ineffective against the more aggressive estrogen receptor negative tumors. A series of experiments have been conducted in our laboratories to test the hypothesis that chemoprevention can be improved by combining SERMS with agents with different mechanisms of action. Such an approach can allow the use of low doses of SERMS and thus reduce their side effects. Literature data provide some support of the protective effects of omega-3 fatty acids against the development of several cancers, including breast cancer. However, the results remain inconsistent which could be due to confounding variables. These confounding variables which have been reported by our group include omega-3:omega-6(n-3:n-6) ratio and caloric intake. A previous study conducted in our laboratories showed that high ratios of omega-3:omega-6 fatty acids(25:1 n-3:n-6) are required to inhibit mammary carcinogenesis in the rat and such high ratios of omega-3:omega-6 fatty acids potentiated the chemopreventive efficacy of tamoxifen. Studies conducted in Chapter 2 were aimed to test the hypothesis that by using a proteomics approach, novel proteins can be identified that can provide insights into the molecular mechanism by which high ratios of omega-3:omega-6 fatty acids inhibit mammary carcinogenesis. We further hypothesize that proteins identified in a minimally invasive fashion can be used for early detection and to monitor the efficacy of the chemopreventive agents. We used an isobaric Tagging for Relative and Absolute Quantitation (iTRAQ) method to provide insights into the mechanism, at the protein level, responsible for the chemopreventive action of the high omega-3:omega-6 fatty acid ratios in the absence and presence of tamoxifen in the 1-methyl-1-nitrosourea(MNU)-induced mammary tumor model in the rat; selective proteins were further validated by western blotting. Compared to control (n-3:n-6, 1:1) diet, both 10:1 and 25:1 n-3:n-6 diets upregulated plasma vitamin D binding protein, gelsolin, and 14-3-3 sigma, reported to have tumor suppressive effects, whereas alpha-1B-glycoprotein which has been reported to be elevated in the serum of breast cancer patients was decreased. Compared to 25:1 n-3:n-6, the 25:1 n-3:n-6 plus tamoxifen diet downregulated apolipoprotein E, haptoglobin, and… Advisors/Committee Members: Karam E El Bayoumy, Dissertation Advisor/Co-Advisor, Arunangshu Das, Committee Member, Thomas E Spratt, Committee Member, Andrea Manni, Committee Member, Mark Kester, Committee Member.

Subjects/Keywords: Docosahexaenoic Acid; Liposome; Breast Cancer Prevention

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Skibinski, C. G. (2015). preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/26720

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Skibinski, Christine G. “preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention.” 2015. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/26720.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Skibinski, Christine G. “preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention.” 2015. Web. 27 Jan 2021.

Vancouver:

Skibinski CG. preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/26720.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Skibinski CG. preclinical investigations into the role of omega-3 fatty acids for breast cancer prevention. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/26720

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

13. Blevins Primeau, Andrea Sascha. UDP-glucuronosyltransferase 2B7 glucuronidation of the active tamoxifen metabolites .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12439

► Tamoxifen (TAM) is a non-steroidal selective estrogen receptor modulator that was approved by the FDA in 1977 for the treatment of breast cancer. Although it… (more)

▼ Tamoxifen (TAM) is a non-steroidal selective estrogen receptor modulator that was approved by the FDA in 1977 for the treatment of breast cancer. Although it is generally well tolerated, significant adverse effects have been reported, including severe hot flashes and an increased risk for venous thromboembolism and endometrial cancer. The phase I metabolism of TAM is primarily performed by CYP2D6 and CYP3A4/5, resulting in the major, active metabolites N-desmethyl-4-hydroxy-tamoxifen (endoxifen) and 4-hydroxy-tamoxifen (4-OH-TAM). Interestingly, CYP2D6 variant genotypes that result in an inactive or less active phenotype results in greater levels of circulating endoxifen and is also associated with clinical outcomes. However, despite adjusting for CYP2D6 genotype, large variability in the circulating levels of endoxifen are still observed, indicating that additional mechanisms, such as other metabolizing pathways, are involved. The UDP-glucuronosyltransferases (UGT) are a super family of phase II metabolizing enzymes that conjugate a glucuronic acid moiety to a substrate, increasing the polarity and thereby facilitating excretion. The present dissertation identified UGTs 1A8, 1A10, and 2B7 as the most active UGTs against trans-endoxifen, in vitro. In addition, UGT2B7 genotype is associated with the glucuronidation phenotype of human liver microsomes (HLM) against both trans-endoxifen and trans-4-OH-TAM. HLM specimens that were hetero- or homozygous for the polymorphic UGT2B7268Tyr allele exhibited a significant decrease in the glucuronidation of trans-endoxifen and trans-4-OH-TAM. A previous study reported the phosphorylation of UGT2B7 by the non-receptor tyrosine kinase, Src, which altered UGT2B7 enzyme activity against the endogenous substrate, 4-hydroxy-estrone. Therefore, the effect of over-expression of Src in UGT2B7 cells on the glucuronidation of trans-endoxifen and trans-4-OH-TAM was examined. Stable over-expression of Src in the wild-type UGT2B7 cells resulted in a significant decrease in the glucuronidation of both TAM metabolites, similar to the level observed in cell lines only stably expressing the polymorphic UGT2B7268Tyr. Interestingly, over-expression of Src in the variant UGT2B7268Tyr cell line did not alter glucuronidation activity. The evidence presented in this dissertation provides additional knowledge of the metabolism of TAM and specifically, how the pharmacogenetics of the UGT family of phase II metabolizing enzymes cause inter-individual differences in TAM metabolism. Advisors/Committee Members: Harriet C Isom, Dissertation Advisor/Co-Advisor, Harriet C Isom, Committee Chair/Co-Chair, Henry Joseph Donahue, Committee Member, Melvin Billinglsey, Ph D, Committee Member, John Peter Richie Jr., Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: pharmacogenetics; drug metabolism; breast cancer; Src; tamoxifen; UGT; polymorphisms

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Blevins Primeau, A. S. (2011). UDP-glucuronosyltransferase 2B7 glucuronidation of the active tamoxifen metabolites . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12439

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Blevins Primeau, Andrea Sascha. “UDP-glucuronosyltransferase 2B7 glucuronidation of the active tamoxifen metabolites .” 2011. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/12439.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Blevins Primeau, Andrea Sascha. “UDP-glucuronosyltransferase 2B7 glucuronidation of the active tamoxifen metabolites .” 2011. Web. 27 Jan 2021.

Vancouver:

Blevins Primeau AS. UDP-glucuronosyltransferase 2B7 glucuronidation of the active tamoxifen metabolites . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/12439.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Blevins Primeau AS. UDP-glucuronosyltransferase 2B7 glucuronidation of the active tamoxifen metabolites . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12439

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

14. Kline, Christina Leah Banta. Potential of Prostate Apoptosis Response protein-4 (Par-4) in colon cancer therapy .

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/12645

► Prostate apoptosis response protein 4 (Par-4) has been shown to induce apoptosis in cancer cells. However, little has been published on the role of Par-4… (more)

▼ Prostate apoptosis response protein 4 (Par-4) has been shown to induce apoptosis in cancer cells. However, little has been published on the role of Par-4 in colon cancer. The purpose of this dissertation is to demonstrate that Par-4 has potential in colon cancer therapy by virtue of its impact on colon cancer cell apoptosis. To achieve this goal, Par-4 was overexpressed in the colon cancer cell line HT29. Par-4-overexpressing cells were more susceptible to apoptosis induced by the colon cancer chemotherapeutic agent 5-fluorouracil (5-FU). Not only does Par-4 have potential in vitro, it also inhibits colon cancer growth in vivo. Par-4 overexpressing tumors grew more slowly and to a smaller mass than wild type HT29 tumors. Caspase-9 cleavage was increased in the Par-4 tumors. In addition to demonstrating the pro-apoptotic effects of overexpressing Par-4 in colon cancer, the potential of activating endogenous Par-4 was explored. In colon cancer, the protein levels and the kinase activity of the nonreceptor tyrosine kinase, c-Src, increase with tumor progression. One of the downstream effectors of c-Src is Akt1. Akt1 has been shown to inhibit the pro-apoptotic activity of Par-4 in prostate cancer cells. Therefore, the possibility of activating Par-4 by inhibiting c-Src was investigated. Colon carcinoma cell lines were treated with the Src kinase inhibitor (4-amino-5-(4-chlorophenyl)-7-(dimethylethyl)pyrazolo[3,4-d]pyrimidine (PP2) in combination with 5-FU. Treating cells with PP2 and 5-FU resulted in reduced interaction of Par-4 with Akt1 and with the scaffolding protein 14-3-3ƒã, and mobilization of Par-4 to the nucleus. Par-4 was shown to interact not only with Akt1 and 14-3-3ƒã, but also with c-Src. Overexpression of c-Src induced the phosphorylation of Par-4 at tyrosine site/s. Thus, endogenous Par-4 can be activated by inhibiting Src kinase with a pharmacological inhibitor and adding a chemotherapeutic agent. The activation of the pro-apoptotic protein Par-4 is a novel mechanism by which apoptosis occurs with a Src kinase inhibitor and 5-FU. In this dissertation, therefore, I demonstrate that a) Par-4 overexpression in combination with the apoptotic and chemotherapeutic agent 5-FU causes cell death in colon cancer cells; and b) endogenous Par-4 can be activated in colon cancer cells by Src inhibition and 5-FU treatment. Thus, the first steps toward attainment of the long-term goal of elucidation of the Par-4 function in colon cancer have been made. With the understanding that Par-4 can be activated in colon cancer, and that Par-4 can promote apoptosis in colon cancer and decrease colon cancer growth, strategies can be designed to exploit the pro-apoptotic activity of Par-4 in colon cancer therapy. Advisors/Committee Members: Rosalyn Bryson Irby, Dissertation Advisor/Co-Advisor, Harriet C Isom, Committee Member, Shantu G Amin, Committee Member, Rosalyn Bryson Irby, Committee Chair/Co-Chair, Thomas E Spratt, Committee Member.

Subjects/Keywords: c-Src; Par-4; prostate apoptosis response protein-4; colon cancer; 5-fluorouracil

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Kline, C. L. B. (2011). Potential of Prostate Apoptosis Response protein-4 (Par-4) in colon cancer therapy . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/12645

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Kline, Christina Leah Banta. “Potential of Prostate Apoptosis Response protein-4 (Par-4) in colon cancer therapy .” 2011. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/12645.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Kline, Christina Leah Banta. “Potential of Prostate Apoptosis Response protein-4 (Par-4) in colon cancer therapy .” 2011. Web. 27 Jan 2021.

Vancouver:

Kline CLB. Potential of Prostate Apoptosis Response protein-4 (Par-4) in colon cancer therapy . [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/12645.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Kline CLB. Potential of Prostate Apoptosis Response protein-4 (Par-4) in colon cancer therapy . [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/12645

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

15. Jones, Nathan Richard. Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism.

Degree: 2012, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/13184

► There is a complex interplay between genetic and environmental factors that determine inter-individual differences in disease disposition and therapeutic response. Drug metabolism pathways have been… (more)

▼ There is a complex interplay between genetic and environmental factors that determine inter-individual differences in disease disposition and therapeutic response. Drug metabolism pathways have been a major focus of pharmacogenetic studies because inter-individual differences in the expression and activity of these enzymes may cause clinically significant effects on the kinetic properties of various drugs. Because of their role in the metabolism of chemical toxins and carcinogens, genetic differences in drug metabolizing enzymes are also associated with risk of diseases such as cancer. There are many factors governing inter-individual variation in drug-metabolizing enzymes including SNPs, epigenetics, alternative splicing events, transcriptional regulation, and post-translational modifications. UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and excretion of endogenous and xenobiotic compounds including drugs and carcinogens. UGT enzymes mediate the phase II conjugation of glucuronic acid to their substrates, thereby increasing substrate polarity and facilitating their excretion. Variations in UGT genes are associated with altered drug metabolism and cancer risk. Some of the genetic factors underlying these associations have been discovered, but often there is wide variability in phenotype within a given genotype. The liver is the organ most commonly associated with metabolism, and most UGTs are expressed in the human liver. Expression in extrahepatic tissues has been less well characterized, even though tissues that form a barrier with the environment, such as aerodigestive and gastrointestinal tract tissues represent an important first line of defense against exposures to xenobiotic compounds. A better understanding of the inter-individual variability and relative abundance of UGT gene expression in different tissues is important as this helps determine the physiological relevance of each UGT enzyme. While many previous studies have used qualitative reverse transcription polymerase chain reaction (RT-PCR) for determining which UGT genes are expressed in different tissues, some quantitative analysis of UGT expression has been performed In studies described in this thesis dissertation, real-time PCR was used to quantify the expression of 16 UGT enzymes in multiple specimens of various normal human tissues including lung, liver, larynx, brain, tongue, floor of mouth, tonsil, esophagus, endometrium, and pancreas. Substantial inter-individual variability in expression was observed in both hepatic and extrahepatic tissues. In extrahepatic tissues, unpredictable expression patterns were frequently observed, in which UGT enzymes expressed in some individuals were not expressed in others. In the liver, there was a high degree of correlation between the expression levels of many UGT enzymes within the same individual, suggesting a common mechanism of transcriptional regulation. The hepatic expression of UGTs is known to be transcriptionally regulated by ligand-activated and… Advisors/Committee Members: Philip Lazarus, Ph D, Dissertation Advisor/Co-Advisor, Philip Lazarus, Ph D, Committee Chair/Co-Chair, Jong Kak Yun, Committee Member, John Peter Richie Jr., Committee Member, Thomas E Spratt, Committee Member, Richard Robert Young, Committee Member.

Subjects/Keywords: UDP-glucuronosyltransferase; expression; transcriptional regulation; alternative splicing; pharmacogenetics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Jones, N. R. (2012). Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/13184

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Jones, Nathan Richard. “Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism.” 2012. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/13184.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Vancouver:

Jones NR. Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism. [Internet] [Thesis]. Penn State University; 2012. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/13184.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Jones NR. Expression of uridinediphosphate glucuronosyltransferase genes: focus on alternative splicing and transcriptional regulatory mechanisms that contribute to interindividual differences in drug and carcinogen metabolism. [Thesis]. Penn State University; 2012. Available from: https://submit-etda.libraries.psu.edu/catalog/13184

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

16. Schweiker, Katrina Lynn. Computational Design and Experimental Characterization of Proteins with Increased Stability and Solubility .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9400

► The ability to design proteins from first principles will provide an efficient way to develop stabilized proteins, which could have a profound impact on a… (more)

▼ The ability to design proteins from first principles will provide an efficient way to develop stabilized proteins, which could have a profound impact on a variety of biotechnological industries. For example, a biosensor made out of stable proteins would be able to be functional in harsh environmental conditions, such as the desert, where sensors made from less stable proteins would not be effective. Another example is that life-saving vaccines made from stable proteins could be stored at ambient temperatures, making it possible to distribute them more effectively to developing nations where refrigeration is not always an option. In addition to addressing the question of what forces govern thermodynamic stability, the field of protein design can also provide insight into the intramolecular interactions that are important for kinetic stability and solubility. In the first part of this dissertation, the SH3 domain of the Fyn tyrosine kinase (FynSH3) was stabilized by the rational design of surface charge-charge interactions. Analysis of the computationally optimized distributions of surface charges showed that the increase in favorable energy per substitution begins to level off after five substitutions. One of the sequences with five substitutions (four charge reversals and one introduction of a new charge) was selected for experimental characterization. Nine additional variants were also characterized to explore the stepwise contributions of these substitutions to the stability of FynSH3. The designed sequence was found to have an increased thermostability of 12 °C and an increase in the free energy of unfolding (ΔG) of 8 kJ/mol, relative to the wild-type protein. These results suggest that a significant increase in stability can be achieved through a small number of amino acid substitutions, and argue for a seminal role of surface charge-charge interactions in modulating protein stability. The second part of this dissertation addresses the question of how important the unfolded state of a protein is for determining its stability and whether it needs to be considered in the design approach. Some of the first attempts to address this issue tried to explain the pH-dependent changes in stability (ΔG) for several different proteins, where it was found that, in order to reproduce experimental data, a statistical (Gaussian polymer chain, GPC) representation of the unfolded state needed to be included in the calculations of ΔG. However, incorporation of this model into our design approach did not significantly improve our predictions. To determine whether this was due to an inability of the Gaussian model to accurately describe the distance distributions, and therefore the energies, observed in structural representations of the unfolded state, the distance distributions for a GPC were compared to those observed in the excluded volume limit (EV) structural libraries of two proteins: ubiquitin and NTL9. For residues that were close in sequence, where the unfolded state energies are the largest, it was found… Advisors/Committee Members: George Makhatadze, Dissertation Advisor/Co-Advisor, George I Makhatadze, Committee Chair/Co-Chair, Judith S Bond, Committee Member, Thomas E Spratt, Committee Member, Philip C. Bevilacqua, Committee Member.

Subjects/Keywords: protein stability; protein engineering; computational design; protein folding

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Schweiker, K. L. (2009). Computational Design and Experimental Characterization of Proteins with Increased Stability and Solubility . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9400

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Schweiker, Katrina Lynn. “Computational Design and Experimental Characterization of Proteins with Increased Stability and Solubility .” 2009. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/9400.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Schweiker, Katrina Lynn. “Computational Design and Experimental Characterization of Proteins with Increased Stability and Solubility .” 2009. Web. 27 Jan 2021.

Vancouver:

Schweiker KL. Computational Design and Experimental Characterization of Proteins with Increased Stability and Solubility . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/9400.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Schweiker KL. Computational Design and Experimental Characterization of Proteins with Increased Stability and Solubility . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9400

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

17. Blome, Matthew. CHARACTERIZATION OF RICIN BINDING TO MULTIVALENT BOVINE SERUM ALBUMIN-BASED NEOGLYCOCONJUGATES .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8208

► Ricin toxin is a potent type 2 ribosome inactivating protein (RIP) from the plant, Ricinus communis. It has the potential to be used as a… (more)

▼ Ricin toxin is a potent type 2 ribosome inactivating protein (RIP) from the plant, Ricinus communis. It has the potential to be used as a bioterrorism agent due to its high toxicity and the relative ease with which it can be obtained/purified. Ricin is a heterodimeric protein consisting of 2 subunits. The A-chain (RTA) is an N-glycosidase that halts protein synthesis by catalyzing the depurination of a specific adenine residue on ribosomal RNA. RTA is linked to the B-chain (RTB) via a single disulphide bridge. RTB is a lectin, containing 2 galactose binding sites ~70Å apart, that plays an essential role in mediating the binding and internalization of the toxin. While the binding of ricin to galactose has been studied, characterization of the binding of ricin to more complex carbohydrate ligands (i.e., glycoproteins and glycolipids) that might be present on the surface of a cell is lacking. In contrast to the low affinity of RTB for monovalent galactose (reported to be between 0.28 and 3.5x 10-4M), its affinity for asialofetuin (ASF) is about 1,000 times greater than it is to monovalent galactose. This observation supports the hypothesis that ricin exhibits multivalency when it adheres to ASF. The goal of this work was to synthesize multivalent carbohydrate ligands, use them to determine whether ricin would bind to them in a multivalent fashion, and to identify general saccharide characteristics that affect binding. To account for the distance between the two galactose binding sites on RTB, bovine serum albumin (BSA) was selected as the oligosaccharide carrier. BSA-based neoglycoconjugates were synthesized and their efficacy as ligands for the toxin monitored using surface plasmon resonance (SPR). The results indicated that ricin did exhibit multivalency when it interacted with appropriately derivatized BSA neoglycoconjugates and that it appeared to bind more efficiently to specific longer chain oligosaccharide ligands than to disaccharides. These observations have important implications for the development of possible antidotes for the treatment of people inadvertently exposed to ricin, for the use of RTB in drug deliver, and for optimization of ricin biosensors. Advisors/Committee Members: Cara Lynne Schengrund, Committee Chair/Co-Chair, Ira Joseph Ropson, Committee Member, Thomas E Spratt, Committee Member, Mark Kester, Committee Member, Michael Pishko, Committee Member.

Subjects/Keywords: glycoconjugate; asialofetuin; surface plasmon resonance; asialo-GM1; ricin; bovine serum albumin; multivalent

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Blome, M. (2008). CHARACTERIZATION OF RICIN BINDING TO MULTIVALENT BOVINE SERUM ALBUMIN-BASED NEOGLYCOCONJUGATES . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8208

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Blome, Matthew. “CHARACTERIZATION OF RICIN BINDING TO MULTIVALENT BOVINE SERUM ALBUMIN-BASED NEOGLYCOCONJUGATES .” 2008. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/8208.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Blome, Matthew. “CHARACTERIZATION OF RICIN BINDING TO MULTIVALENT BOVINE SERUM ALBUMIN-BASED NEOGLYCOCONJUGATES .” 2008. Web. 27 Jan 2021.

Vancouver:

Blome M. CHARACTERIZATION OF RICIN BINDING TO MULTIVALENT BOVINE SERUM ALBUMIN-BASED NEOGLYCOCONJUGATES . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/8208.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Blome M. CHARACTERIZATION OF RICIN BINDING TO MULTIVALENT BOVINE SERUM ALBUMIN-BASED NEOGLYCOCONJUGATES . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8208

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

18. Nadaraia-Hoke, Shorena. STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES.

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/10156

► Polyamines are ubiquitous, physiological cations that are essential for a wide range of functions in normal cells, including cell proliferation, differentiation, signal transduction, and apoptosis.… (more)

▼ Polyamines are ubiquitous, physiological cations that are essential for a wide range of functions in normal cells, including cell proliferation, differentiation, signal transduction, and apoptosis. Polyamines interact and stabilize various negatively charged macromolecules such as cellular nucleic acids, alter membrane structure and act as modulators of ion channels. Cells utilize complex metabolic systems and multiple compensatory mechanisms to ensure polyamine homeostasis and, even though their functions at the molecular level are not completely understood, polyamines are critical to cell survival. In mammals, the polyamines, spermidine and spermine, are synthesized by two aminopropyltransferases, spermidine- and spermine-synthases, respectively. Both enzymes utilize decarboxylated S-adenosylmethionine and produce a second product, 5’-methylthioadenosine. Recent structural studies have revealed that the catalytic domains of these enzymes share a common fold. However, potentially, they are regulated in different ways. Spermidine synthase has a gatekeeping loop that is thought to control access to the active site, whereas spermine synthase does not have a gatekeeping loop but contains an additional N-terminal domain that may have a regulatory role. In the presented studies, several biophysical methods were used to begin to understand how these enzymes are regulated. Thermotoga maritima spermidine synthase and human spermine synthase were used as model systems. Specifically, the effect of substrates, products, and inhibitors on spermidine synthase were examined using high-throughput high-resolution deuterium exchange mass spectrometry and isothermal titration calorimetry. In addition, N-terminal deletions of human spermidine synthase and single point variants, which are found in Snyder Robinson Syndrome, were characterized to investigate their effect on the tertiary structure and domain organization. The results of these studies point towards a critical role of oligomerization in each enzyme and suggest the existence of novel regulatory mechanisms controlling their activities in the polyamine biosynthetic pathway. Advisors/Committee Members: Dr Flanagan, Dissertation Advisor/Co-Advisor, John Michael Flanagan Jr., Committee Chair/Co-Chair, Anthony Edward Pegg, Committee Member, Kent Eugene Vrana, Committee Member, Ira Joseph Ropson, Committee Member, Thomas E Spratt, Committee Member.

Subjects/Keywords: polyamines; spermidine synthase; spermine synthase; isothermal titration calorimetry; snyder-robinson syndrome

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Nadaraia-Hoke, S. (2009). STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/10156

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Nadaraia-Hoke, Shorena. “STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES.” 2009. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/10156.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Nadaraia-Hoke, Shorena. “STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES.” 2009. Web. 27 Jan 2021.

Vancouver:

Nadaraia-Hoke S. STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES. [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/10156.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Nadaraia-Hoke S. STRUCTURAL AND THERMODYNAMIC CHARACTERIZATION OF SPERMIDINE AND SPERMINE SYNTHASES. [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/10156

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

19. De Cotiis, Daniel A. FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION .

Degree: 2009, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/9804

► Neuronal Calcium Sensor 1 (NCS-1) is an acidic, highly helical protein (MW 23 kDa), which is involved in a variety of cellular pathways including exocytosis… (more)

▼ Neuronal Calcium Sensor 1 (NCS-1) is an acidic, highly helical protein (MW 23 kDa), which is involved in a variety of cellular pathways including exocytosis and G-protein linked receptor desensitization. NCS-1 contains an N-terminal myristoylation modification, as well as three EF-hand domains which bind calcium with moderate to high affinity. These attributes have been previously shown to affect the structural and functional behavior of the protein. In order to better characterize these changes, a protocol presented here has been designed and optimized to produce large quantities of recombinant N-myristoylated and unmodified NCS-1 in E. coli. Using this technique, novel mutants showing a spectrum of functional deficiencies are expressed, isolated and then characterized by a number of assays. The large quantities of homogenous protein produced are shown to be suitable for biophysical studies using a variety of in vivo and in vitro techniques. Contrary to what would be expected for a protein of small size, NCS-1 interacts with a wide diversity of other proteins. One mechanism by which NCS-1 could assume this functional assortment of roles is by forming higher order homo-complexes. Experimental results presented here demonstrate that NCS-1 is capable of forming calcium dependent homo-dimer complexes. The propensity for self-association is enhanced by N-terminal myristoylation. In the absence of ligand, all three functional EF-hand sites must be intact in order for NCS-1 dimerization to occur. As NCS-1 plays a wide diversity of roles in the cell, the formation of homo-dimers may have pronounced functional implications. NCS-1 forms a signaling complex with the D2 dopamine receptor (D2R) and other downstream effectors, ultimately regulating desensitization of the receptor in response to dopamine signaling. As a result, this regulatory complex may be involved in a number of neurological disease states including schizophrenia and bipolar disorder. A better understanding of the biophysical and regulatory details of this complex will have important implication for understanding disease pathology and exploring novel drug treatments. Using a fluorescent peptide substrate in a fluorescence polarization assay, the equilibrium binding behavior of the NCS-1 / D2R interaction is described here. The formation of the NCS-1 / D2R complex is shown to be calcium dependent and involve the NCS-1 dimer. The contribution of the various EF-hand domains to binding is also investigated, and a discrete role in dimerization and binding is implied for each pair of EF-hand domains. The outcomes of these experiments could be used to optimize a large format drug screen scaled from this assay system, which could ultimately isolate lead compounds for the treatment of D2R related diseases. Advisors/Committee Members: John Michael Flanagan Jr., Dissertation Advisor/Co-Advisor, John Michael Flanagan Jr., Committee Chair/Co-Chair, Maria Christine Bewley, Committee Member, Robert G Levenson, Committee Member, Thomas E Spratt, Committee Member, Ira Joseph Ropson, Committee Member.

Subjects/Keywords: neuronal calcium sensor 1; signalplex; myristoylation; dopaminergic signalling

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

De Cotiis, D. A. (2009). FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/9804

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

De Cotiis, Daniel A. “FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION .” 2009. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/9804.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

De Cotiis, Daniel A. “FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION .” 2009. Web. 27 Jan 2021.

Vancouver:

De Cotiis DA. FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION . [Internet] [Thesis]. Penn State University; 2009. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/9804.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

De Cotiis DA. FROM PROTEIN TO SIGNALPLEX: THE ROLE OF CALCIUM BINDING AND MYRISTOYLATION IN NEURONAL CALCIUM SENSOR-1 STRUCTURE AND FUNCTION . [Thesis]. Penn State University; 2009. Available from: https://submit-etda.libraries.psu.edu/catalog/9804

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

20. Facompre, Nicole Danielle. Organoselenium-mediated alteration of prostate cancer cell signaling pathways .

Degree: 2010, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11123

► Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer related death in men in the United States. The lack of… (more)

▼ Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer related death in men in the United States. The lack of treatment for “worried well” patients with prostatic intraepithelial neoplasia (a premalignant condition) combined with issues of recurrence and hormone resistance present significant obstacles to prostate cancer survivorship. The long latency of prostate cancer provides opportunity to intervene with mechanistically-based agents at various stages of disease progression. A number of signaling cascades have been shown to play important roles in prostate cancer development and progression, including the androgen receptor, PI3K/Akt, and mammalian target of rapamycin (mTOR) signaling pathways. Crosstalk between the androgen receptor and Akt pathways is thought to contribute to progression and hormone refractory disease. Studies have also implicated the mammalian target of rapamycin (mTOR) signaling pathway in the progression of prostate cancer and its transition to androgen independence, suggesting mTOR as a potential target for new therapies. Selenium, an essential nutrient and known antioxidant, has been shown in epidemiologic and preclinical studies to be protective against prostate cancer. However, clinical intervention trials with selenium have thus far had contradictory outcomes and the anti-cancer mechanisms of selenium compounds are not well understood. Studies consistently show that dose and form are critical factors in the actions of selenium compounds. In the present investigation we compare the effects of two structurally distinct organoselenium compounds naturally occurring selenomethionine (SM) and synthetic 1,4-phenylenebis(methylene)selenocyanate (p-XSC) on cell growth, apoptosis, and signaling in androgen responsive (AR) and androgen independent (AI) human prostate cancer cells. We have found that, in contrast to SM, p-XSC dose-dependently inhibits viability, induces apoptosis, and modulates critical signaling molecules in both AR and AI cells. p-XSC effectively inhibits androgen receptor expression and transcriptional activity, Akt phosphorylation, and Akt-specific phosphorylation of the androgen receptor. We also show that p-XSC preferentially inhibits mTOR complex 2 (mTORC2) signaling in AI cells, a novel potential target for selenium in prostate cancer. Based on these findings, we hypothesized that the combination of p-XSC with rapamycin, which primarily targets mTOR complex 1 (mTORC1), may be a superior approach to inhibit prostate cancer cell growth than either agent alone. Drug combination strategies can offer a number of advantages to single-agent therapies including the enhancement of efficacy, the reduction of dose and toxicity, and the management of drug resistance. Our data show that inhibition of AI cell viability and mTOR signaling is significantly enhanced by combining p-XSC and rapamycin, compared with each agent individually. We propose that these agents achieve this effect, in part, by targeting the two distinct arms of the… Advisors/Committee Members: Karam E El Bayoumy, Dissertation Advisor/Co-Advisor, Karam E El Bayoumy, Committee Chair/Co-Chair, Raghu Sinha, Committee Member, Jeffrey Maurice Peters, Committee Member, Thomas E Spratt, Committee Member, Sergei A Grigoryev, Committee Member.

Subjects/Keywords: androgen receptor; selenium; prostate cancer; Akt

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Facompre, N. D. (2010). Organoselenium-mediated alteration of prostate cancer cell signaling pathways . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11123

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Facompre, Nicole Danielle. “Organoselenium-mediated alteration of prostate cancer cell signaling pathways .” 2010. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/11123.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Facompre, Nicole Danielle. “Organoselenium-mediated alteration of prostate cancer cell signaling pathways .” 2010. Web. 27 Jan 2021.

Vancouver:

Facompre ND. Organoselenium-mediated alteration of prostate cancer cell signaling pathways . [Internet] [Thesis]. Penn State University; 2010. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/11123.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Facompre ND. Organoselenium-mediated alteration of prostate cancer cell signaling pathways . [Thesis]. Penn State University; 2010. Available from: https://submit-etda.libraries.psu.edu/catalog/11123

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Penn State University

21. Emmert, Sans Wellington. Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8177

► ABSTRACT Levels of dietary selenium are inversely associated with cancer risk in humans, and selenium has played a major role in the field of chemoprevention.… (more)

▼ ABSTRACT Levels of dietary selenium are inversely associated with cancer risk in humans, and selenium has played a major role in the field of chemoprevention. In particular, the organoselenium agents 1,4-phenylenebis(methylene)seleno-cyanate (p-XSC) and its glutathione conjugate, p-XSeSG, are effective in preventing cancers at numerous sites, including the lung in rodent models. In the A/J mouse lung, p-XSC is highly effective in inducing glutathione (GSH), but mechanisms are not well understood. Glutathione is the most abundant antioxidant in animals, and is an important mechanistic factor in chemoprevention. Glutamate cysteine ligase (GCL) is the rate-limiting enzyme responsible for GSH production. Transcriptional regulation of GCL occurs via antioxidant response elements (ARE) in the promoter regions of its genes. Induction of the ARE is in turn regulated by stabilization and nuclear translocation of the transcription factor, Nuclear factor-erythroid 2-Related Factor 2 (Nrf2). Furthermore, the extracellular signal-regulated kinase (ERK) pathway has been shown to play a role in Nrf2 stabilization. Potent chemopreventive phytochemicals, such as sulforaphane (SFN), have been shown to act largely through the Nrf2/ARE pathway. The potential relevance of Nrf2 to GSH induction led to the hypothesis that Nrf2 activation may be involved in organoselenium-mediated induction of GSH, and this was investigated in vivo and in several cell culture models. Here we show that dietary p-XSC induces Nrf2, p-ERK, GCL and GSH in the lung of the Fisher rat, suggesting involvement of Nrf2 and the ERK pathway in GSH induction. In addition, GSH and GCL were induced by p-XSeSG in the Fisher rat. In cell culture studies we observed that p-XSC and p-XSeSG activate an ARE luciferase reporter in an Nrf2-dependent manner. It was also shown that p-XSeSG induced GSH in vitro, and is less toxic than p-XSC. The dependence of GCL induction by p-XSeSG upon Nrf2 was confirmed in wildtype and Nrf2-mutanted Mouse Embryonic Fibroblasts (MEF). These results suggest that p-XSC acts through the Nrf2 pathway in vivo, and that p-XSeSG may be the metabolite responsible for such activation, thus offering p-XSeSG as a less toxic, yet highly efficacious inducer of GSH. Isothiocyanate compounds such as SFN are among the most potent Nrf2 inducers known. We hypothesized that substitution of sulfur with selenium in the isothiocyanate functional group of SFN would result in an isoselenocyanate compound (SFN-isoSe) with enhanced Nrf2 induction capability. Here we show that SFN-isoSe activates an ARE-luciferase reporter in HepG2 cells more potently than SFN. It was also found that SFN-isoSe induces GCL and GSH in MEF cells in an Nrf2-dependent manner. Finally, we provide evidence that SFN-isoSe is more effective in killing HepG2 cancer cells, yet is less toxic to non-cancer MEF cells, than is SFN. These data support our hypothesis, and suggest that SFN-isoSe may be a highly effective chemoprotective agent in vivo. Taken together, these results support the hypothesis that… Advisors/Committee Members: John Peter Richie Jr., Committee Chair/Co-Chair, Karam E El Bayoumy, Committee Member, Thomas E Spratt, Committee Member, Kent Eugene Vrana, Committee Member, Craig Matthew Meyers, Committee Member.

Subjects/Keywords: glutathione; organoselenium; Nrf2

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Emmert, S. W. (2008). Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8177

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Emmert, Sans Wellington. “Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds .” 2008. Thesis, Penn State University. Accessed January 27, 2021. https://submit-etda.libraries.psu.edu/catalog/8177.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Emmert, Sans Wellington. “Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds .” 2008. Web. 27 Jan 2021.

Vancouver:

Emmert SW. Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Jan 27]. Available from: https://submit-etda.libraries.psu.edu/catalog/8177.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Emmert SW. Role of Nuclear factor-erythroid 2-Related Factor 2 in Glutamate Cysteine Ligase Induction by Organoselenium Compounds . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8177

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

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Open Access Theses and Dissertations