+publisher:"Penn State University" +contributor:("Michael Verderame, Committee Member")

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Penn State University

1. Kren, Nancy Porterfield. Characterization of Functional Regions of OGFr.

Degree: 2015, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/26247

► The Opioid Growth Factor (OGF)-OGF receptor (OGFr) axis is present and tonically active in animal and human cancer cell lines, as well as human tumors.… (more)

▼ The Opioid Growth Factor (OGF)-OGF receptor (OGFr) axis is present and tonically active in animal and human cancer cell lines, as well as human tumors. The OGF-OGFr pathway tonically mediates cell replication in cancer, with OGF serving as an autocrine-produced inhibitory pentapeptide. The inhibitory action of OGF on cell replication requires that OGF bind to OGFr, traffic into the nucleus to upregulate inhibitory kinases, p16 and p21 that act to stall the progression from G1-S phase of the cell cycle. Little is currently known about the functional regions required for this function. To begin to characterize the functional regions of OGFr, mutations in OGFr identified in cancer samples were characterized. Two mutations identified in cancer samples, S378I and R444H, were characterized with respect to their effects on localization of the receptor, as well as their ability to alter DNA synthesis. R444H demonstrated a significant decrease in the nuclear/cytoplasmic ratio while S378I showed no change. Both mutations demonstrated a loss of response to OGF and the long-acting opioid receptor antagonist naltrexone (NTX) in growth assays. R444H also demonstrated a loss of inhibition in DNA synthesis, while S378I showed no significant change compared to OGFr in the BrdU assay. These data demonstrate that cancer mutations such as R444H are capable of altering the inhibitory function of OGFr, while other mutations such as S378I may be capable of altering the response to the ligand OGF or the antagonist NTX. These data contribute to the understanding of the functionally required regions of OGFr and warrant further characterization of mutations identified in cancer samples.OGFr has three nuclear localization signals (NLS) that have previously been characterized. OGFr requires at least two of the three NLSs for entry into the nucleus and for inhibition of cell proliferation. When NLSs were mutated, OGFr was excluded from the nucleus and proliferation inhibition was lost. The nuclear export of OGFr is currently unknown. In this study, endogenous OGFr, as well as exogenously expressed OGFr-EGFP, demonstrated significant nuclear accumulation in response to leptomycin B (LMB), an inhibitor of CRM1 dependent nuclear export, suggesting OGFr is exported in a CRM1 dependent manner. One leucine rich sequence fitting the consensus sequence for nuclear export signals (NES) was identified. To better characterize this sequence, the associated leucines, L217 L220 L223 and L225, were mutated to alanine in isolation as well as in combinations. All of the mutations resulted in decreased nuclear accumulation. In support of decreased nuclear localization, subNES demonstrated a loss of inhibition. When the proposed NES was fused to EGFP, NES-EGFP, it responded to LMB, indicating this sequence is capable of functioning as an export signal in isolation. To investigate why the sequence functions differently in isolation than in the context of the full-length protein, the localization of subNES was evaluated in the presence of MG132, a potent inhibitor of… Advisors/Committee Members: Patricia McLaughlin, Dissertation Advisor/Co-Advisor, Michael Verderame, Committee Member, Ira Joseph Ropson, Committee Member, Lisa M Shantz, Committee Member, Samuel Shaomin Zhang, Committee Member.

Subjects/Keywords: OGFr; NES; Tandem Repeats

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APA (6^th Edition):

Kren, N. P. (2015). Characterization of Functional Regions of OGFr. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/26247

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):

Kren, Nancy Porterfield. “Characterization of Functional Regions of OGFr.” 2015. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/26247.

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

MLA Handbook (7^th Edition):

Kren, Nancy Porterfield. “Characterization of Functional Regions of OGFr.” 2015. Web. 03 Mar 2021.

Vancouver:

Kren NP. Characterization of Functional Regions of OGFr. [Internet] [Thesis]. Penn State University; 2015. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/26247.

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

Council of Science Editors:

Kren NP. Characterization of Functional Regions of OGFr. [Thesis]. Penn State University; 2015. Available from: https://submit-etda.libraries.psu.edu/catalog/26247

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

Penn State University

2. Donahue, Renee N. PATHWAYS TARGETED BY THE OGF-OGFr AXIS ARE DETERMINANTS IN THE PROGRESSION OF HUMAN OVARIAN CANCER.

Degree: 2011, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/11689

► Ovarian cancer is the leading cause of death from gynecological malignancies, and is the 5th leading cause of cancer related mortality among women. An estimated… (more)

▼ Ovarian cancer is the leading cause of death from gynecological malignancies, and is the 5th leading cause of cancer related mortality among women. An estimated 225,000 new cases are diagnosed each year worldwide, resulting in 140,200 deaths annually. Approximately 90% of primary ovarian cancers are epithelial in origin, and the most common presentation (75%) is in the advanced stages (stage III/IV). Cytoreductive surgery and adjuvant chemotherapy serve as the major treatment modalities. Initial clinical response is excellent; however, nearly 65% of advanced-staged patients relapse within 2 years of initial therapy. Once ovarian cancer recurs, all subsequent treatments are palliative. The cellular and molecular events involved in ovarian cancer pathogenesis need to be defined, and major improvements in treatment will require new therapies based on exploitation of biological pathways. Dysregulation of cell proliferation is an integral part of the ovarian cancer phenotype. One native biological regulatory system of cell replication in normal cells and a variety of cancers is the opioid growth factor (OGF) and its receptor, OGFr. Chemically termed [Met5]-enkephalin, OGF is a constitutively active opioid peptide that is autocrine produced and secreted, and interacts with OGFr to delay the G1/S interface of the cell cycle by modulating cyclin-dependent kinase inhibitory (CKI) pathways, without affecting cell survival. The studies depicted in this thesis were aimed at establishing the role of the OGF-OGFr axis in the modulation of cell proliferation and determining the repercussions of modulating this axis on human ovarian cancer both in vitro and in vivo. The first study evaluated the presence, mechanism, and role of the OGF-OGFr axis on the modulation of the growth of OVCAR-3 and SKOV-3 human ovarian cancer cell lines. OGF and OGFr were present and functional. Exogenous OGF was observed to have a dose-dependent, serum-independent, reversible and receptor-mediated inhibitory action on cell proliferation that was dependent on RNA and protein synthesis. The repressive effect of OGF on cell proliferation also was also observed in CAOV-3 and HEY ovarian cancer cell lines. Endogenous OGF was found to be constitutively produced and tonically active on cell replicative activities, with neutralization of this peptide accelerating cell proliferation. Silencing of OGFr by siRNA technology stimulated cell replication, and abolished the inhibitory actions of exogenous OGF, documenting its integral role in mediating the effects of endogenous and exogenous OGF. The mechanism of OGF-OGFr action on DNA synthesis was related to the CKI pathways because knockdown of p16 and p21 in OVCAR-3 cells, and p21 in SKOV-3 cells eliminated OGF¡¦s inhibitory effect on growth. These data are the first to report that the OGF-OGFr system is a native biological regulator of cell proliferation in human ovarian cancer cells using an in vitro model system. The next study determined whether OGF inhibits tumor growth in mice with… Advisors/Committee Members: Patricia Mclaughlin, Dissertation Advisor/Co-Advisor, Patricia J Mc Laughlin, Committee Chair/Co-Chair, Ian Stuart Zagon, Committee Member, Ronald Paul Wilson, Committee Member, Robert Harold Bonneau, Committee Member, Michael Verderame, Committee Member.

Subjects/Keywords: Ovarian Cancer; Opioids; Opioid Growth Factor (OGF); Opioid Growth Factor Receptor (OGFr); Naltrexone (NTX); Low Dose Naltrexone (LDN)

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APA (6^th Edition):

Donahue, R. N. (2011). PATHWAYS TARGETED BY THE OGF-OGFr AXIS ARE DETERMINANTS IN THE PROGRESSION OF HUMAN OVARIAN CANCER. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/11689

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):

Donahue, Renee N. “PATHWAYS TARGETED BY THE OGF-OGFr AXIS ARE DETERMINANTS IN THE PROGRESSION OF HUMAN OVARIAN CANCER.” 2011. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/11689.

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

MLA Handbook (7^th Edition):

Donahue, Renee N. “PATHWAYS TARGETED BY THE OGF-OGFr AXIS ARE DETERMINANTS IN THE PROGRESSION OF HUMAN OVARIAN CANCER.” 2011. Web. 03 Mar 2021.

Vancouver:

Donahue RN. PATHWAYS TARGETED BY THE OGF-OGFr AXIS ARE DETERMINANTS IN THE PROGRESSION OF HUMAN OVARIAN CANCER. [Internet] [Thesis]. Penn State University; 2011. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/11689.

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

Council of Science Editors:

Donahue RN. PATHWAYS TARGETED BY THE OGF-OGFr AXIS ARE DETERMINANTS IN THE PROGRESSION OF HUMAN OVARIAN CANCER. [Thesis]. Penn State University; 2011. Available from: https://submit-etda.libraries.psu.edu/catalog/11689

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

Penn State University

3. Cheng, Fan. OGF-OGFR AXIS AND ITS INHIBITORY ACTIONS ON CELL CYCLE PROGRESSION .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7289

► Opioid growth factor (OGF) is an endogenous opioid peptide ([Met5]-enkephalin) that interacts with the OGF receptor (OGFr), and serves as a tonically active negative growth… (more)

▼ Opioid growth factor (OGF) is an endogenous opioid peptide ([Met5]-enkephalin) that interacts with the OGF receptor (OGFr), and serves as a tonically active negative growth factor in neoplasia. Previous studies showed that OGF inhibits the growth of human head and neck squamous cell carcinoma (HNSCC) cells and pancreatic cancer cells in vitro and in vivo, and is targeted to cell proliferation. However, the mechanism by which OGF inhibits cell replication was not clear. The studies described within this thesis were directed towards defining the molecular mechanisms of OGF inhibitory action. A number of unique findings are presented here. In SCC1 HNSCC cell cultures synchronized with nocodazole, flow cytometry revealed that OGF treatment (10-6 M) resulted in fewer cells exiting the G1 phase of the cell cycle in comparison to controls (p<0.05). Subsequent studies showed that OGF decreased the phosphorylation of retinoblastoma protein (Rb) (p<0.05) without changing the total Rb expression. Reduced phosphorylated Rb was correlated with reduced cdk4 kinase activity while the total cdk4 expression did not change. Moreover, OGF treatment increased cyclin-dependent kinase inhibitor (CKI) p16 protein expression 2-fold in comparison to controls (p<0.05), but had no significant effect on p15, p18, p19, p21 or p27 protein expression. Western blot analysis did not detect p57 protein in the SCC1 cell line. Blockade of OGF-OGFr interactions with the short-acting opioid antagonist, naloxone (NAL), demonstrated that increased expression of p16 protein by OGF was completely abolished by concomitant administration of OGF and NAL. NAL alone had no effect on p16 expression suggesting that this regulation of p16 was an opioid receptor mediated event. Moreover, OGF treatment increased p16 protein expression in comparison to controls (p<0.05) in CAL27 and SCC4 HNSCC cell lines, demonstrating the ubiquitous nature of this observation. Inhibition of p16 (INK4a) activation by p16 specific siRNA blocked OGF inhibitory action on proliferation of SCC1, CAL-27 and SCC4 HNSCC cells. Cultures treated with negative control siRNA, which had no effect on p16 expression, did not block OGFâ€™s growth inhibitory action. Collectively, these results indicate that the receptor-mediated, growth inhibitory effects of the OGF-OGFr axis in HNSCC cells are associated with induction of p16/cdk4 resulting in decreased Rb phosphorylation. These data revealed that the target of cell proliferative inhibitory action of OGF in human HNSCC cells is by the way of cyclin dependent kinase inhibitory pathways, specifically, the p16 pathway. Because many human HNSCC tumors retain p16, OGF may be a valuable therapeutic agent in this setting. Alternatively, pancreatic cancer cells have frequently lost p16 gene expression, and thus other CKI pathways were examined for their role with OGF inhibition of pancreatic cancer growth. BxPC-3 human pancreatic adenocarcinoma cell cultures were synchronized with nocodazole, and flow cytometry revealed that OGF treatment (10-6 M) resulted… Advisors/Committee Members: Patricia Mclaughlin, Committee Chair/Co-Chair, Ian Stuart Zagon, Committee Member, Michael Verderame, Committee Member, Xuwen Peng, Committee Member.

Subjects/Keywords: cell cycle; OGF

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APA (6^th Edition):

Cheng, F. (2008). OGF-OGFR AXIS AND ITS INHIBITORY ACTIONS ON CELL CYCLE PROGRESSION . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7289

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):

Cheng, Fan. “OGF-OGFR AXIS AND ITS INHIBITORY ACTIONS ON CELL CYCLE PROGRESSION .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/7289.

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

MLA Handbook (7^th Edition):

Cheng, Fan. “OGF-OGFR AXIS AND ITS INHIBITORY ACTIONS ON CELL CYCLE PROGRESSION .” 2008. Web. 03 Mar 2021.

Vancouver:

Cheng F. OGF-OGFR AXIS AND ITS INHIBITORY ACTIONS ON CELL CYCLE PROGRESSION . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/7289.

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

Council of Science Editors:

Cheng F. OGF-OGFR AXIS AND ITS INHIBITORY ACTIONS ON CELL CYCLE PROGRESSION . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7289

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

Penn State University

4. Scheifele, Lisa Z. From the ribosome to the membrane: Subcellular trafficking of the Rous sarcoma virus Gag polyprotein.

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/6221

► Retroviruses such as human immunodeficiency virus (HIV) and human T-cell leukemia virus (HTLV) are the etiological agents of immunodeficiency diseases and cancer. We have been… (more)

▼ Retroviruses such as human immunodeficiency virus (HIV) and human T-cell leukemia virus (HTLV) are the etiological agents of immunodeficiency diseases and cancer. We have been studying the subcellular targeting of the Gag protein of Rous sarcoma virus (RSV), one of the first simple retroviruses identified. The Gag protein directs assembly at the plasma membrane and incorporates the viral genome through association with a cis-acting packaging element in the viral RNA. Although functional domains within Gag that mediate the assembly process have been well defined, the activity of these motifs has not been well correlated with the trafficking of Gag throughout the cell during assembly. We have identified distinct subcellular targeting motifs within the Rous sarcoma virus Gag protein that may influence the retroviral assembly pathway. Within the Gag membrane-binding domain, we have identified an alpha helix that is crucial for plasma membrane targeting of Gag. When this helix is deleted, the Gag protein accumulates at intracellular membranes. Yet membrane affinity is not diminished, indicating that membrane binding and plasma membrane targeting of the RSV Gag polyprotein are genetically separable. We have also identified both a nuclear targeting signal within the N-terminal MA domain of Gag and a nuclear export signal (NES) within the p10 domain. Expression of dominant-negative nuclear pore proteins redistributes the Gag protein from a cytoplasmic and plasma membrane localization to an almost exclusively nuclear localization, confirming that Gag both enters and exits the nucleus. We have further identified the soluble receptor that mediates the cytoplasmic localization of Gag; treatment of virus-expressing cells with leptomycin B, a specific inhibitor of the CRM-1 export pathway results in sequestration of the Gag protein within the nucleus. Single amino-acid substitutions within a leucine-rich cluster in the p10 domain of Gag result in accumulation of the protein within the nucleus, confirming the localization of the Gag NES within the p10 region. Interestingly, we find that the NES sequence is highly conserved among avian retroviruses; when naturally occurring variations within this sequence are recreated in the RSV Gag protein, NES function is retained, while artificial substitutions predicted to retain NES function do not. We have sought to identify additional cellular proteins that influence the import and export of Gag from the nucleus by employing the powerful genetic system developed in the yeast Saccharomyces cerevisiae. Expression of Gag linked to a tandem GFP reporter reveals a localization to the cytoplasm of yeast cells with an accumulation in the nucleus not seen at steady-state in avian cells. Not only is the dwell time between the nucleus and cytoplasm altered, but the nuclear export pathway is perturbed as well; yeast cells do not show an enhanced accumulation of Gag proteins within the nucleus following leptomycin B treatment, suggesting that the Crm1 pathway may not be the predominant export… Advisors/Committee Members: Leslie Joan Parent, Committee Chair/Co-Chair, Rebecca C Craven, Committee Member, James E Hopper, Committee Member, Craig Matthew Meyers, Committee Member, Michael Verderame, Committee Member.

Subjects/Keywords: retrovirus; Gag; nucelar transport; Crm1

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

APA (6^th Edition):

Scheifele, L. Z. (2008). From the ribosome to the membrane: Subcellular trafficking of the Rous sarcoma virus Gag polyprotein. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/6221

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):

Scheifele, Lisa Z. “From the ribosome to the membrane: Subcellular trafficking of the Rous sarcoma virus Gag polyprotein.” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/6221.

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

MLA Handbook (7^th Edition):

Scheifele, Lisa Z. “From the ribosome to the membrane: Subcellular trafficking of the Rous sarcoma virus Gag polyprotein.” 2008. Web. 03 Mar 2021.

Vancouver:

Scheifele LZ. From the ribosome to the membrane: Subcellular trafficking of the Rous sarcoma virus Gag polyprotein. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/6221.

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

Council of Science Editors:

Scheifele LZ. From the ribosome to the membrane: Subcellular trafficking of the Rous sarcoma virus Gag polyprotein. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/6221

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

Penn State University

5. Basehore, Heather Kenney. CHARACTERIZATION OF THE EARLY INTERACTIONS ON THE FOLDING PATHWAY OF THE ILEAL LIPID-BINDING PROTEIN BY 19F-NMR .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7834

► Determining whether two structurally related proteins fold via similar mechanisms is an important question in structural biology. Intracellular lipid-binding proteins (iLBP’s) are a large family… (more)

▼ Determining whether two structurally related proteins fold via similar mechanisms is an important question in structural biology. Intracellular lipid-binding proteins (iLBP’s) are a large family of proteins that share a common ?-barrel structure in spite of very low sequence similarities. One member of this family, intestinal fatty acid-binding protein (IFABP) has been shown to fold by a mechanism of specific hydrophobic collapse in a core structural region. These kinetic folding intermediates differ from intermediates observed for the structurally related protein, ileal lipid-binding protein (ILBP). There is some evidence that both proteins initiate folding by the same mechanism, but that stable folding intermediates do not accumulate to the same level for both. The proposed folding mechanism of IFABP is supported by equilibrium unfolding studies by 19F-NMR. Residues in contact with each other in the native protein retain elements of structure at denaturant concentrations much higher than the unfolding midpoint concentrations. This is manifested in the 19F-NMR spectra in the form of NMR spectral changes that differ in response to denaturant depending on the residue’s role in the folding pathway. Similar analysis of ILBP demonstrates that some residues in this protein also display non-uniform behavior by 19F-NMR with increasing denaturant, although the residues responsible for this behavior were not identified in the initial analysis. By labeling the protein with 19F one residue at a time, assignment of the peak resonances for each 19F-Phe in ILBP have now been made. The results of these 19F-NMR experiments reveal that some of the interactions that occur early in folding may be conserved, but the specific nature of the initiating reactions differs for these two related proteins. Advisors/Committee Members: Ira Joseph Ropson, Committee Chair/Co-Chair, Dr Michael Pishko, Committee Member, Cara Lynne Schengrund, Committee Member, Michael Verderame, Committee Member.

Subjects/Keywords: b-sheet proteins; 19F-NMR; protein folding

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

APA (6^th Edition):

Basehore, H. K. (2008). CHARACTERIZATION OF THE EARLY INTERACTIONS ON THE FOLDING PATHWAY OF THE ILEAL LIPID-BINDING PROTEIN BY 19F-NMR . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7834

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):

Basehore, Heather Kenney. “CHARACTERIZATION OF THE EARLY INTERACTIONS ON THE FOLDING PATHWAY OF THE ILEAL LIPID-BINDING PROTEIN BY 19F-NMR .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/7834.

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

MLA Handbook (7^th Edition):

Basehore, Heather Kenney. “CHARACTERIZATION OF THE EARLY INTERACTIONS ON THE FOLDING PATHWAY OF THE ILEAL LIPID-BINDING PROTEIN BY 19F-NMR .” 2008. Web. 03 Mar 2021.

Vancouver:

Basehore HK. CHARACTERIZATION OF THE EARLY INTERACTIONS ON THE FOLDING PATHWAY OF THE ILEAL LIPID-BINDING PROTEIN BY 19F-NMR . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/7834.

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

Council of Science Editors:

Basehore HK. CHARACTERIZATION OF THE EARLY INTERACTIONS ON THE FOLDING PATHWAY OF THE ILEAL LIPID-BINDING PROTEIN BY 19F-NMR . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7834

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

Penn State University

6. Rowzee, Anne Marie. EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/7861

► The ultimate function of the mammary gland is to nourish newborns to sustain mammalian life post-partum. Development and differentiation of the mammary gland occurs postnatally… (more)

▼ The ultimate function of the mammary gland is to nourish newborns to sustain mammalian life post-partum. Development and differentiation of the mammary gland occurs postnatally under the control of a complex system of hormonal and environmental cues making the mammary gland an important model of study for both developmental biology and endocrinology. Furthermore, breast cancer is the “number one cause of cancer death in Hispanic women” and the “second most common cause of cancer death in white, black, Asian/Pacific Islander and American Indian/Alaska Native women” according to the Centers for Disease Control and Prevention. These statistics make it clear that ongoing research in both breast cancer and normal mammary gland development is imperative to women’s health. The primary cause of breast cancer is transformation of mammary epithelial cells (MECs) that result in unregulated cell proliferation and subsequent mammary carcinomas. Several components of the insulin-like growth factor (IGF) system, the IGF ligands and the IGF-type I receptor (IGF-1R) in particular, regulate both normal and transformed MEC growth. Previous studies from our laboratory examined expression of the IGF ligands and the IGF-1R in normal mammary gland development and demonstrated that the IGF ligands and the IGF-1R are expressed in distinct patterns during normal development. Subsequent analysis of receptor affinity for IGF ligands demonstrated that the insulin receptor isoform A (IR-A) is an IGF-II-sensitive signaling receptor and furthermore, that hybrid receptors consisting of equal parts IGF-1R and insulin receptor (IR), preferentially bind IGF ligands. Herein, we have developed and tested a quantitative PCR assay to accurately measure IGF-1R, IR-A and IR isoform-B (IR-B) expression on the same scale. We have used this assay to quantify mRNA expression of IGF sensitive receptors in primary MECs during mammary gland development. These data demonstrate that IR isoforms are expressed at much higher levels than the IGF-1R at all times. Subsequent protein analysis demonstrated that due to this disproportion, at least 49% of IGF-1R is present as part of a hybrid receptor during pregnancy stages. We next provide preliminary data that demonstrate preferential activation of the IGF-1R rather than hybrid receptors by IGF-I in vivo. Furthermore, we demonstrate that insulin stimulates IGF-1R activation in vivo, either by stimulating classic IGF-1R or IGF-1R present in a hybrid receptor. The importance of IGF-1R signaling in MEC development is further supported by microarray analysis of a MEC-specific conditional deletion of the IGF-1R during post-pubertal development. These data suggest a functional role for IGF-1R signaling via the PI3K/Akt pathway in regulating expression of cell cycle regulatory molecules. In the final section of this thesis, we present in vitro data that support the findings of the microarray analysis and demonstrate that activation of the PI3K/Akt/mammalian target of rapamycin pathway stimulates cell cycle… Advisors/Committee Members: Teresa Wood, Committee Chair/Co-Chair, Edward Joseph Gunther, Committee Chair/Co-Chair, Maricarmen Planas Silva, Committee Member, Michael Verderame, Committee Member, Andrea Manni, Committee Member.

Subjects/Keywords: Insulin-like growth factor receptor; Insulin receptor; Mammary epithelial cells; Quantitative PCR; Insulin-like growth factors; Epidermal growth factor

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

APA (6^th Edition):

Rowzee, A. M. (2008). EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7861

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):

Rowzee, Anne Marie. “EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/7861.

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

MLA Handbook (7^th Edition):

Rowzee, Anne Marie. “EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH .” 2008. Web. 03 Mar 2021.

Vancouver:

Rowzee AM. EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/7861.

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

Council of Science Editors:

Rowzee AM. EXPRESSION AND FUNCTION OF INSULIN-LIKE GROWTH FACTOR SIGNALING RECEPTORS IN MAMMARY EPITHELIAL CELL GROWTH . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7861

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

Penn State University

7. Draper, Jeremiah Michael. Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase .

Degree: 2008, Penn State University

URL: https://submit-etda.libraries.psu.edu/catalog/8983

► Many important signaling proteins require the post-translational addition of fatty acid chains for their proper subcellular localization and function. One such modification is the addition… (more)

▼ Many important signaling proteins require the post-translational addition of fatty acid chains for their proper subcellular localization and function. One such modification is the addition of palmitoyl moieties by enzymes known as palmitoyl acyltransferases (PATs). Substrates for PATs include C-terminally farnesylated proteins, such as H- and N-Ras, as well as N-terminally myristoylated proteins, such as multiple Src-related tyrosine kinases. Since many of these proteins are involved in intracellular signaling pathways that drive cellular survival and proliferation, and their activity is predicated on specific subcellular localizations, the enzymes that catalyze their posttranslational modifications are attractive drug targets. However, the primary focus of selective drug development in this arena has been on the process of farnesylation, partly because the farnesyltransferases have been cloned, characterized, and used in screens to develop inhibitors. In contrast, the identification and characterization of human PATs has been hindered by the lack of defined assays to characterize these enzymes, thus preventing the direct validation of the involvement of these enzymes in diseases such as cancer. Current assays to measure palmitoylation activity are functional; however, they employ fractionated cell lysates and are relatively low-throughput. These methods, though useful, are insufficient to directly measure PAT activity in intact cells, which would be useful in the identification of human PATs and studies of the regulation of these enzymes. Thus, we sought to develop quantitative and efficient cellular assays to characterize PAT activity in intact cells. To develop these assays, we used cell-permeable, fluorescently-labeled lipidated peptides that mimic the PAT recognition domains of farnesylated and myristoylated proteins. These PAT substrate mimetics are accumulated by SKOV3 cells in a saturable and time-dependent manner. Although both peptides are rapidly palmitoylated, the SKOV3 cells have a greater capacity to palmitoylate the myristoylated peptide than the farnesylated peptide. Confocal microscopy indicated that the palmitoylated peptides co-localized with Golgi and plasma membrane markers, whereas the corresponding non-palmitoylatable peptides accumulate in the Golgi but did not traffic to the plasma membrane. These results indicate that the lipidated peptides provide useful cellular probes for quantitative and compartmentalization studies of protein palmitoylation in intact cells. Exposure of SKOV3 cells to the peptides did not cause cytotoxicity at any concentration within the maximal 2 hr timeframe of the peptide uptake, palmitoylation, and intracellular localization experiments. However, when exposed to the peptides for 72 hrs cytotoxicity did occur in a palmitoylatable and motif-specific manner. Specifically, the non-palmitoylatable forms of both peptides caused minimal cytotoxicity even at the highest concentrations tested. In contrast, the palmitoylatable forms of both peptides exhibited cytotoxicity of… Advisors/Committee Members: Charles Smith, Dissertation Advisor/Co-Advisor, Charles D Smith, Committee Chair/Co-Chair, Kent Eugene Vrana, Committee Member, Michael Verderame, Committee Member, Jong Kak Yun, Committee Member, Melvin Lee Billingsley, Committee Member.

Subjects/Keywords: localization; transformation; Palmitoyl acyltransferase; drug target

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APA (6^th Edition):

Draper, J. M. (2008). Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase . (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/8983

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):

Draper, Jeremiah Michael. “Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase .” 2008. Thesis, Penn State University. Accessed March 03, 2021. https://submit-etda.libraries.psu.edu/catalog/8983.

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

MLA Handbook (7^th Edition):

Draper, Jeremiah Michael. “Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase .” 2008. Web. 03 Mar 2021.

Vancouver:

Draper JM. Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase . [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Mar 03]. Available from: https://submit-etda.libraries.psu.edu/catalog/8983.

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

Council of Science Editors:

Draper JM. Identification of Human DHHC20 as a Transforming Palmitoyl Acyltransferase . [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/8983

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

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