Functional modulation of the cytosolic chaperonin TRiC/CCT through small molecule inhibition
Abstract/Contents
- Abstract
- Cellular homeostasis heavily relies on the proper protein folding and maintenance of the proteome by molecular folding machines known as chaperones. In cells undergoing higher proliferation rates, the folding demands are higher, for which reason cancer cells are considered to be addicted to chaperones to meet the higher protein folding supply. TRiC/CCT is a molecular chaperonin that is increasingly linked to oncogenesis not only due to its client substrates, but also because its subunits are amplified in many tumor tissues. While other chaperones such as Hsp70 and Hsp90 have been targeted for drug development, studies to identify TRiC inhibitors have been limited by the 1MDa complex purification difficulties. In this work, we have identified a novel small molecule that inhibits the TRiC ATPase cycle from a high-throughput screen of an > 100,000 compound library. The topmost inhibitor was found to impact the obligate actin folding activity by the chaperonin. Furthermore, we found that TRiC inhibitor treatment in prostate cancer cells expressing the androgen receptor disrupted cytoskeletal integrity, cell morphology and viability in comparison to cells lacking the hormone receptor. These findings shed light on a mechanism by which inhibitors perturb TRiC cycling, leading to poor actin folding, and a consequent decrease in cell viability from a weakened actin filament network. The results represent the development of novel tools to understand the proteostasis network as well as a foundation to target TRiC therapeutically.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Serrano Lachapel, Ivana L |
|---|---|
| Degree supervisor | Frydman, Judith |
| Thesis advisor | Frydman, Judith |
| Thesis advisor | Dixon, Scott James, 1977- |
| Thesis advisor | Gozani, Or Pinchas |
| Thesis advisor | Wandless, Thomas |
| Degree committee member | Dixon, Scott James, 1977- |
| Degree committee member | Gozani, Or Pinchas |
| Degree committee member | Wandless, Thomas |
| Associated with | Stanford University, School of Humanities and Sciences |
| Associated with | Stanford University, Department of Biology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Ivana L. Serrano Lachapel. |
|---|---|
| Note | Submitted to the Department of Biology. |
| Thesis | Thesis Ph.D. Stanford University 2023. |
| Location | https://purl.stanford.edu/gp611pn1791 |
Access conditions
- Copyright
- © 2023 by Ivana L Serrano Lachapel
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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