Dissertation
Sigma1 as a ligand-operated scaffolding protein that regulates the activity of oncogenic driver and immunomodulatory proteins in cancer cells
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2018
DOI:
https://doi.org/10.17918/4zta-5r57
Abstract
Due to rapid proliferation and the corresponding increased demand for protein production, cancer cells depend on the support systems, including chaperones and scaffolding proteins, that enable these activities. Scaffolds have no enzymatic or signaling activity; however, they physically interact with other proteins to assemble, localize, and regulate signaling complexes. Sigma1 (also known as sigma-1 receptor) is a unique integral membrane protein that resides primarily in the cellular secretory pathway wherein it contributes to the maintenance of protein homeostasis. Sigma1 has no known signaling or enzymatic activities, and its functions have been defined largely by its regulation of associated proteins. The studies presented in this dissertation support the concept of Sigma1 as a pharmacologically controllable scaffolding protein that helps to stabilize and allosterically regulate the signaling activities of associated proteins that promote tumor growth and survival. The impact of Sigma1 modulation on three distinct types of tumor-promoting proteins was identified and characterized: the androgen receptor (AR, a nuclear hormone receptor); ErbB receptors (integral membrane receptor tyrosine kinases); and programmed death ligand 1 (PD-L1, an integral membrane immune checkpoint protein). Sigma1 physically associated with and regulated the localization, stability, and function of these proteins. Pharmacological modulation of Sigma1 resulted in the inhibition of cancer cell proliferation and survival in vitro and suppression of tumor growth in vivo, in part by co-opting cellular protein homeostasis pathways on which these proteins depend. Altogether, these data reveal a novel mechanism by which Sigma1 acts as a ligand-operated scaffolding protein that allosterically modulates the trafficking, stability, and signaling of certain tumor-promoting factors.
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Details
- Title
- Sigma1 as a ligand-operated scaffolding protein that regulates the activity of oncogenic driver and immunomodulatory proteins in cancer cells
- Creators
- Christina Marie Sanders - DU
- Contributors
- Felix J. Kim (Advisor) - Drexel University (1970-)Paul McGonigle (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 192 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- College of Medicine; Pharmacology and Physiology; Drexel University
- Other Identifier
- 8230; 991014632442804721