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Temple University

1. Ritchie, Michael. TRANSCRIPTIONAL AND MOLECULAR CONTROL OF CALCIUM SIGNALING.

Degree: PhD, 2012, Temple University

Biochemistry

The extensive relationship between modulation of intracellular Ca2+ content and the control of cell proliferation (Boynton et al. 1974; Whitfield et al. 1979; Berridge and Irvine 1984), differentiation (Bridges et al. 1981; Holliday et al. 1991) and death (Orrenius et al. 2003) has led to much examination into the relationship between Ca2+ signaling pathways and the onset of various pathological conditions, including cancer, cardiac hypertrophy, immunodeficiency, neurodegeneration. Control of Ca2+ signals is achieved via an extensive combination of pumps, channels and exchangers which regulate the concentration of Ca2+ within not only the cytosol but also all intracellular compartments. Accordingly, a great deal of research has focused on the mechanisms which regulate these channels and pumps, and recently the primary mechanism for Ca2+ influx in non-excitable cells has been identified. This process, termed Store-operated calcium entry (SOCe), is a key evolutionarily conserved mechanism whereby decreases in endoplasmic reticulum Ca2+ content (sensed by the ER Ca2+ sensor, STIM1) leads to the influx of Ca2+ across the plasma membrane through the Orai family of Ca2+ channels. However, many questions remain about how this Ca2+ signaling pathway is regulated. In this thesis, I provide evidence regarding the transcriptional and molecular mechanisms regulating SOCe. Initial studies in my thesis work aimed to identify some of the key events leading to dysregulation of Ca2+ homeostasis in the kidney specific pediatric malignancy, Wilms' Tumor. I found that STIM1 expression levels and SOCe signals are significantly reduced in Primary Wilms' Tumor samples. Subsequent analysis of these phenomena led me to the finding that STIM1 expression is under the control of the transcription factors Wilms' Tumor Suppressor 1 (WT1) and Early Growth Response 1 (EGR1). Subsequent investigations were carried out with the purpose to assess how activation of the EGR1 transcription factor alters long term Ca2+ signals. Indeed, I found that receptor-mediated activation of EGR1 leads to induction of STIM1 expression and increases in SOCe. However, unexpectedly through these analyses, I propose a novel role for STIM1 that STIM1 interacts with the Plasma Membrane Ca2+ ATPase (PMCA) through its C-terminal proline-rich domain and reduces PMCA-mediated Ca2+ clearance, effectively creating local, augmented Ca2+ gradients. This coordinated control of Ca2+ entry and exit from the cell has wide-ranging implications for Ca2+ signaling in multiple cell types.

Temple University – Theses

Advisors/Committee Members: Soboloff, Jonathan, Gill, Donald L., Soprano, Dianne R., Giangiacomo, Kathleen, Freedman, Bruce D..

Subjects/Keywords: Biochemistry; Molecular biology; Calcium Signaling; PMCA; STIM1

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

APA (6th Edition):

Ritchie, M. (2012). TRANSCRIPTIONAL AND MOLECULAR CONTROL OF CALCIUM SIGNALING. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,211071

Chicago Manual of Style (16th Edition):

Ritchie, Michael. “TRANSCRIPTIONAL AND MOLECULAR CONTROL OF CALCIUM SIGNALING.” 2012. Doctoral Dissertation, Temple University. Accessed September 25, 2020. http://digital.library.temple.edu/u?/p245801coll10,211071.

MLA Handbook (7th Edition):

Ritchie, Michael. “TRANSCRIPTIONAL AND MOLECULAR CONTROL OF CALCIUM SIGNALING.” 2012. Web. 25 Sep 2020.

Vancouver:

Ritchie M. TRANSCRIPTIONAL AND MOLECULAR CONTROL OF CALCIUM SIGNALING. [Internet] [Doctoral dissertation]. Temple University; 2012. [cited 2020 Sep 25]. Available from: http://digital.library.temple.edu/u?/p245801coll10,211071.

Council of Science Editors:

Ritchie M. TRANSCRIPTIONAL AND MOLECULAR CONTROL OF CALCIUM SIGNALING. [Doctoral Dissertation]. Temple University; 2012. Available from: http://digital.library.temple.edu/u?/p245801coll10,211071

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