Using CDK4/6 inhibitors to identify novel regulators of the RB pathway
Abstract/Contents
- Abstract
- The initiation of cell division is a fundamental cellular process that integrates a large number of intra- and extra-cellular inputs. In mammalian cells, D-type cyclins (cyclin D1, D2, and D3, together "cyclin D") couple these inputs to the decision to initiate DNA replication. Increased levels of cyclin D promote cell cycle progression by activating cyclin-dependent kinases 4 and 6 (CDK4/6), which in turn phosphorylate and inactivate the retinoblastoma protein (RB) to drive cell cycle entry. Accordingly, increased levels and activity of cyclin D and their associated kinases are strongly linked to unchecked cell proliferation and tumor development. Despite this central role in cell cycle progression, the mechanisms regulating cyclin D levels remain incompletely understood. Here, we identify AMBRA1 as the main regulator of cyclin D protein degradation. We first identified AMBRA1 in a genome-wide CRISPR/Cas9 loss-of-function screen investigating the genetic basis of response to chemical CDK4/6 inhibition. AMBRA1 loss results in high protein levels of cyclin D in cells and in mice. These high levels of cyclin D reshuffle the cyclin-CDK complexes active in G1 to promote proliferation and increase tolerance to CDK4/6 inhibition. AMBRA1 loss also promotes the development of lung adenocarcinoma in mouse models, and low levels of AMBRA1 correlate with worse survival in lung adenocarcinoma patients. We then identified the mechanistic link between AMBRA1 and cyclin D . AMBRA1 acts as a substrate receptor for the Cullin 4 E3 ligase complex to promote ubiquitylation and proteasomal degradation of the three D-type cyclins. Thus, AMBRA1 is a previously unrecognized regulator of the cell cycle, directly limiting cyclin D protein levels and thereby influencing the development of cancer as well as the response of cancer cells to CDK4/6 inhibitors.
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 | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Chaikovsky, Andrea Christine |
|---|---|
| Degree supervisor | Sage, Julien |
| Thesis advisor | Sage, Julien |
| Thesis advisor | Attardi, Laura |
| Thesis advisor | Jackson, Peter K. (Peter Kent) |
| Thesis advisor | Skotheim, Jan, 1977- |
| Degree committee member | Attardi, Laura |
| Degree committee member | Jackson, Peter K. (Peter Kent) |
| Degree committee member | Skotheim, Jan, 1977- |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Andrea C. Chaikovsky. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/gk798xs8144 |
Access conditions
- Copyright
- © 2021 by Andrea Christine Chaikovsky
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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