The mechanism of helix-based docking between cyclin D-Cdk4,6 and the retinoblastoma protein
Abstract/Contents
- Abstract
- The cyclin-dependent kinases Cdk4 and Cdk6 form complexes with D-type cyclins to drive cell proliferation. A well-known target of cyclin D-Cdk4,6 is the retinoblastoma protein, Rb, which inhibits cell cycle progression until its inactivation by phosphorylation. However, the role of Rb phosphorylation by cyclin D-Cdk4,6 in cell-cycle progression is unresolved because Rb can be phosphorylated by other cyclin-Cdks and cyclin D-Cdk4,6 has other targets involved in cell division. In this dissertation, I describe the work and discoveries that I, the Skotheim lab, and many collaborators have made. We first examine the Rb protein for unique cyclin docking interactions (Chapter 2) and show that cyclin D-Cdk4,6 docks one side of an alpha helix in the Rb C-terminus, which is not recognized by cyclins E, A, and B. This helix-based docking mechanism is shared by the p107 and p130 Rb-family members across metazoans. Mutation of the Rb C-terminal helix prevents its phosphorylation, promotes G1 arrest, and enhances Rb's tumor suppressive function. We then examined the role of cyclin D in helix-based docking (Chapter 3) and identified the region on cyclin D1 responsible for helix-based docking of Rb. When helix-based docking is disrupted by mutation of the C-terminal cyclin box fold alpha2' helix on cyclin D1, Rb phosphorylation is lost and cells arrest in G1. This discovery identifies a role for the cyclin D C-terminal cyclin box fold substrate docking and another mechanism to potentially inhibit cyclin D-Cdk4,6 activity in cancer. More broadly, this work conclusively demonstrates that the cyclin D-Rb interaction drives cell division and expands the diversity of known cyclin-based protein docking mechanisms.
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 | 2020; ©2020 |
| Publication date | 2020; 2020 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Topacio, Benjamin Reyes |
|---|---|
| Degree supervisor | Skotheim, Jan, 1977- |
| Thesis advisor | Skotheim, Jan, 1977- |
| Thesis advisor | Cyert, Martha S, 1958- |
| Thesis advisor | Lipsick, Joseph Steven, 1955- |
| Thesis advisor | Sage, Julien |
| Degree committee member | Cyert, Martha S, 1958- |
| Degree committee member | Lipsick, Joseph Steven, 1955- |
| Degree committee member | Sage, Julien |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Benjamin Reyes Topacio. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2020. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2020 by Benjamin Reyes Topacio
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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