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Thesis
A role for Sigma1 in the maintenance of ER protein homeostasis through the modulation of VCP-mediated ubiquitin-selective autophagy
Master of Science (M.S.), Drexel University
14 Jun 2012
DOI:
https://doi.org/10.17918/etd-3896
Abstract
The sigma1 receptor (Sigma1) is an integral endoplasmic reticulum (ER) membrane protein that is highly expressed in several cancer cell types. We have shown that certain Sigma1 selective small molecule ligands disrupt ER protein homeostasis in prostate, liver, pancreas, and several breast cancer cell lines. However, as Sigma1 has no known intrinsic signaling activity, the mechanism of action of this ligand-mediated ER stress remains unclear. We hypothesize that identification of Sigma1-associated proteins will provide insight into its role in ER protein homeostasis as well as elucidate the mechanism of action of Sigma1 selective ligands. Thus, we have developed an affinity-purification method that will enable us to isolate and characterize Sigma1 and its associated proteins as well as Sigma1 protein complexes from several tumor cell lines. Consistent with our data demonstrating that Sigma1 ligands modulate ER protein homeostasis, these proteins are known to function in ER protein processing, transport, or degradation. Using this approach, we have identified a direct physical association of Sigma1 with the protein VCP (valosin containing protein), and treatment with a Sigma1-selective small molecule ligand results in dissociation of VCP from Sigma1. We find that treatment with this Sigma1 ligand mediates the reversible sequestration of ubiquitinated ER proteins into autophagosomes, and this ligand mediated ubiquitin-selective autophagy is Sigma1 dependent. This effect correlates with the subcellular co-localization of VCP, ubiquitinated proteins, as well as known components involved in the formation and assembly of autophagosomes. This thesis proposes that Sigma1 associates with VCP to maintain proper ER protein processing, and that Sigma1-selective ligands can be used to modulate this association.
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Details
- Title
- A role for Sigma1 in the maintenance of ER protein homeostasis through the modulation of VCP-mediated ubiquitin-selective autophagy
- Creators
- Anil Kolur - DU
- Contributors
- Felix J. Kim (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems (1997-2026); Drexel University
- Other Identifier
- 3896; 991014632381504721