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Vanderbilt University
1.
Bruntz, Ronald Chase.
Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.
Degree: PhD, Pharmacology, 2014, Vanderbilt University
URL: http://hdl.handle.net/1803/10427 
► The production of bioactive lipids by phospholipases has long been appreciated as an important mode of cellular communication. Phospholipase D (PLD) enzymes hydrolyze phosphatidylcholine to…
(more)
▼ The production of bioactive lipids by phospholipases has long been appreciated as an important mode of cellular communication. Phospholipase D (PLD) enzymes hydrolyze phosphatidylcholine to generate a choline headgroup and the important lipid second messenger, phosphatidic acid (PtdOH). PLD family members are found in a diverse range of species from viruses to humans and regulate many important physiological processes including cytoskeletal rearrangements, cell migration, immune response, and cell proliferation. As such, PLD promotes oncogenic processes and elevated PLD activity has been documented in many types of cancerous tissue and derived cell lines. PLD activity is associated with cell cycle progression, resistance to apoptotic stimuli, and tumor cell invasion, but the molecular mechanisms of these PLD-mediated processes are largely uncharacterized. The goal of this project was to identify and characterize novel PLD-protein complexes in order to further understand the mechanisms by which PLD promotes cancer growth and survival. In this dissertation, PLD-derived PtdOH is demonstrated to be a novel regulator of pro-survival Akt kinase in glioblastoma cells by regulating membrane recruitment and activation of Akt. Inhibition of PLD enzymatic activity and subsequent Akt activation decreases GBM cell viability by specifically inhibiting autophagic flux. Additionally, PLD is shown to interact with a number of metabolic enzymes and a potential role for the regulation of cellular bioenergetics in GBM is explored. The results of this research provide mechanistic insight into PLD-mediated cancer cell survival.
Advisors/Committee Members: Brian E. Wadzinski (committee member), Daniel C. Liebler (committee member), H. Alex Brown (committee member), Heidi E. Hamm (committee member), Kevin C. Ess (committee member), John H. Exton (Committee Chair).
Subjects/Keywords: phospholipase D; phosphatidic acid; cancer; Akt; cell signaling; autophagy
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APA (6th Edition):
Bruntz, R. C. (2014). Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10427
Chicago Manual of Style (16th Edition):
Bruntz, Ronald Chase. “Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.” 2014. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/10427.
MLA Handbook (7th Edition):
Bruntz, Ronald Chase. “Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival.” 2014. Web. 15 Jan 2021.
Vancouver:
Bruntz RC. Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. [Internet] [Doctoral dissertation]. Vanderbilt University; 2014. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/10427.
Council of Science Editors:
Bruntz RC. Insights into the Molecular Mechanisms of Phospholipase D-Mediated Cancer Cell Survival. [Doctoral Dissertation]. Vanderbilt University; 2014. Available from: http://hdl.handle.net/1803/10427
Vanderbilt University
2.
Popescu, Daniela Catalina.
Regulation of the TRP calcium channel by eye-PKC in Drosophila.
Degree: PhD, Pharmacology, 2006, Vanderbilt University
URL: http://hdl.handle.net/1803/14765
► The transient receptor potential (TRP) ion channels are implicated in diverse physiological processes, however their regulatory mechanisms remain obscure. In Drosophila, TRP is a calcium…
(more)
▼ The transient receptor potential (TRP) ion channels are implicated in diverse physiological processes, however their regulatory mechanisms remain obscure. In Drosophila, TRP is a calcium channel mediating the light-dependent depolarization of photoreceptor cells. TRP associates with inactivation-no-afterpotential D (INAD), a scaffolding protein that forms a macromolecular complex by also tethering a phospholipase Cbeta, NORPA, and an eye-specific protein kinase C, eye-PKC. It is well established that eye-PKC regulates deactivation of the visual response. Moreover, deactivation is regulated by the interaction between INAD and TRP, as abrogation of this interaction in InaDp215 results in slow deactivation similar to that of inaCp209 lacking eye-PKC. Eye-PKC was shown previously to phosphorylate TRP in vitro. In this thesis we investigated the mechanism by which eye-PKC regulates TRP to achieve fast deactivation of the visual signaling. We identified Ser982 of TRP as an eye-PKC phosphorylation site by an in vitro kinase assay. We show that phosphorylation of TRP by eye-PKC is dependent on both eye-PKC and INAD, suggesting that INAD acts to anchor eye-PKC to TRP. Importantly, we show by mass spectrometry that TRP is indeed phosphorylated by eye-PKC in vivo: phosphorylated peptides spanning Ser982 were observed in TRP isolated from light adapted wild-type but not from inaCp209 flies. To gain insight into the functional significance of phosphorylation at Ser982 of TRP, we generated transgenic flies expressing a modified TRP containing an Ala substitution at Ser982. We demonstrated that transgenic flies exhibited abnormal deactivation, indicating that phosphorylation of TRP at Ser982 by eye-PKC is critical for deactivation of the visual signaling. Interestingly, the slow deactivation defect in the transgenic flies is similar to that of InaDp215 in which TRP fails to associate with INAD, suggesting that the deactivation defect of InaDp215 is due to a loss of TRP phosphorylation by eye-PKC. Taken together, these findings support the notion that the INAD macromolecular complex is important for termination of the visual response, as it positions eye-PKC in close proximity to TRP to promote fast inactivation of the TRP channel.
Advisors/Committee Members: Bih-Hwa Shieh (committee member), Louis DeFelice (committee member), Heidi Hamm (committee member), John H. Exton (committee member), David Hachey (committee member), Brian Wadzinski (Committee Chair).
Subjects/Keywords: Photoreceptors; INAD; TRP; PKC; Drosophila; ion channel; Protein kinase C
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APA (6th Edition):
Popescu, D. C. (2006). Regulation of the TRP calcium channel by eye-PKC in Drosophila. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/14765
Chicago Manual of Style (16th Edition):
Popescu, Daniela Catalina. “Regulation of the TRP calcium channel by eye-PKC in Drosophila.” 2006. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/14765.
MLA Handbook (7th Edition):
Popescu, Daniela Catalina. “Regulation of the TRP calcium channel by eye-PKC in Drosophila.” 2006. Web. 15 Jan 2021.
Vancouver:
Popescu DC. Regulation of the TRP calcium channel by eye-PKC in Drosophila. [Internet] [Doctoral dissertation]. Vanderbilt University; 2006. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/14765.
Council of Science Editors:
Popescu DC. Regulation of the TRP calcium channel by eye-PKC in Drosophila. [Doctoral Dissertation]. Vanderbilt University; 2006. Available from: http://hdl.handle.net/1803/14765
Vanderbilt University
3.
Erdogan, Mete.
R-Ras Proteins and TGF-Beta in Cancer.
Degree: PhD, Cancer Biology, 2008, Vanderbilt University
URL: http://hdl.handle.net/1803/10878
► The development of cancer in humans is characterized by the accumulation of genetic alterations that either enhance or diminish activity in signaling pathways mediating cellular…
(more)
▼ The development of cancer in humans is characterized by the accumulation of genetic alterations that either enhance or diminish activity in signaling pathways mediating cellular growth and proliferation. Over time these alterations gradually transform normal cells into malignant cells with aberrant properties. This process of transformation gives rise to cancerous cells no longer under control by natural growth-regulatory mechanisms within the body. The signaling pathways that govern cell growth and proliferation are mediated in part through the activity of regulatory GTPases, and the R-Ras family of GTPases has been implicated in the promotion of tumorigenesis.
Here we investigate the transforming properties of two highly homologous members of the R-Ras family. R-Ras and TC21(R-Ras2) are two Ras-related GTPases with the potential to induce oncogenic transformation in mammalian cells. Despite their similarities, these proteins have distinct functions and differ in their ability to transform cells in vitro and induce tumor
formation in vivo. We hypothesized that these differences in tumorigenicity resulted from differential activation of signaling pathways mediating growth and proliferation downstream of R-Ras and TC21. Using mammary epithelial cells we show that TC21 is significantly more transforming than R-Ras, and we demonstrate that distinct signaling events are required for these oncogenes to induce cellular transformation.
Transforming growth factor-beta (TGF-â) is a key regulator of cell growth in the body. TGF-â can cooperate with oncogenic members of the Ras superfamily to trigger cell transformation, yet it is unknown whether TGF-â exhibits this type of cooperative behavior with R-Ras and TC21. We investigated this possibility and found R-Ras-transformation to be highly dependent on TGF-â-signaling, while TC21-transformation was less dependent. Through these studies we have generated an in vitro/in vivo model of tumorigenesis that can be used to investigate the molecular events mediating R-Ras and TC21-induced transformation. Importantly, this model will be useful for identifying structural domains that mediate the oncogenic activity of R-Ras proteins, and for testing the efficacy of small molecule inhibitors as potential cancer therapeutics.
Advisors/Committee Members: Dr. Neil Bhowmick (committee member), Dr. John H. Exton (committee member), Dr. Roy Zent (committee member), Dr. Harold L. Moses (Committee Chair).
Subjects/Keywords: R-Ras; Transformation; Cancer; TGF-Beta; TC21; Transforming growth factors-beta – Physiological effect; RAS oncogenes; Carcinogenesis – Molecular aspects
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APA ·
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APA (6th Edition):
Erdogan, M. (2008). R-Ras Proteins and TGF-Beta in Cancer. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10878
Chicago Manual of Style (16th Edition):
Erdogan, Mete. “R-Ras Proteins and TGF-Beta in Cancer.” 2008. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/10878.
MLA Handbook (7th Edition):
Erdogan, Mete. “R-Ras Proteins and TGF-Beta in Cancer.” 2008. Web. 15 Jan 2021.
Vancouver:
Erdogan M. R-Ras Proteins and TGF-Beta in Cancer. [Internet] [Doctoral dissertation]. Vanderbilt University; 2008. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/10878.
Council of Science Editors:
Erdogan M. R-Ras Proteins and TGF-Beta in Cancer. [Doctoral Dissertation]. Vanderbilt University; 2008. Available from: http://hdl.handle.net/1803/10878
Vanderbilt University
4.
Henage, Lee Gardner.
Kinetic analysis of phospholipase D: Allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides.
Degree: PhD, Pharmacology, 2006, Vanderbilt University
URL: http://hdl.handle.net/1803/10502
► In mammalian cells, phospholipase D activity is tightly regulated by diverse cellular signals including hormones, neurotransmitters, and growth factors. Multiple signaling pathways converge upon phospholipase…
(more)
▼ In mammalian cells, phospholipase D activity is tightly regulated by diverse cellular signals including hormones, neurotransmitters, and growth factors. Multiple signaling pathways converge upon phospholipase D to modulate cellular actions such as cell growth, shape and secretion. The kinetic properties of protein kinase C and G-protein regulation of mammalian phospholipase D1 (PLD1) were examined in order to better understand interactions between PLD1 and its regulators. Activation by Arf-1, RhoA, Rac1, Cdc42, protein kinase Ca, and phosphatidylinositol 4,5-bisphosphate displayed surface dilution kinetics, but these effectors modulated different kinetic parameters. A kinetic description of PLD1 activation by multiple modulators reveals a mechanism for apparent synergy between activators. These findings suggest a role for PLD1 as a signaling node, in which integration of convergent signals occurs within discrete locales of the cellular membrane.
Advisors/Committee Members: Heidi E. Hamm (committee member), Terry R. Lybrand (committee member), Albert H. Beth (committee member), John H. Exton (committee member), H. Alex Brown (committee member), Vsevolod V. Gurevich (Committee Chair).
Subjects/Keywords: phospholipase d; enzymology; G-protein; protein kinase C; ADP-ribosylation factor
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APA ·
Chicago ·
MLA ·
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CSE |
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Manager
APA (6th Edition):
Henage, L. G. (2006). Kinetic analysis of phospholipase D: Allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/10502
Chicago Manual of Style (16th Edition):
Henage, Lee Gardner. “Kinetic analysis of phospholipase D: Allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides.” 2006. Doctoral Dissertation, Vanderbilt University. Accessed January 15, 2021.
http://hdl.handle.net/1803/10502.
MLA Handbook (7th Edition):
Henage, Lee Gardner. “Kinetic analysis of phospholipase D: Allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides.” 2006. Web. 15 Jan 2021.
Vancouver:
Henage LG. Kinetic analysis of phospholipase D: Allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides. [Internet] [Doctoral dissertation]. Vanderbilt University; 2006. [cited 2021 Jan 15].
Available from: http://hdl.handle.net/1803/10502.
Council of Science Editors:
Henage LG. Kinetic analysis of phospholipase D: Allosteric modulation by monomeric GTPases, protein kinase C, and polyphosphoinositides. [Doctoral Dissertation]. Vanderbilt University; 2006. Available from: http://hdl.handle.net/1803/10502
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