DOI

https://doi.org/10.25772/JQEG-SS40

Author ORCID Identifier

https://orcid.org/0000-0002-9973-3639

Defense Date

2022

Document Type

Thesis

Degree Name

Doctor of Philosophy

Department

Clinical and Translational Sciences

First Advisor

Larisa Litovchick, MD/PhD

Second Advisor

Joyce Lloyd, PhD

Third Advisor

Jennifer Koblinski, PhD

Fourth Advisor

David Gewirtz, PhD

Fifth Advisor

Xianjun Fang, PhD

Abstract

The cell cycle is a highly regulated process that ensures the timely and accurate division of cells. Events of the normal cell cycle fall under two categories - positive and negative regulatory mechanisms. The first category, positive regulatory machinery, includes active protein complexes of cyclins in association with their partnering cyclin-dependent kinases (cyclin/CDK), which mediate series of phosphorylation events that relay a cell cycle progression from one stage to the next. The second category, the negative regulatory mechanisms, include the checkpoint controls consisting of the retinoblastoma (RB) family of proteins, some of which can form a transcriptional repressor complex DREAM. These negative regulators work in coordination to halt cell cycle progression until completion of critical regulatory events. Additionally, the primary cell cycle machinery is influenced by a multitude of upstream factors such as viral oncoproteins, growth factors, as well as the cell-cell contacts. However, it is not fully established how such different stimuli can converge on the cell cycle machinery. Here we explore the mechanisms of cell cycle deregulation with relevance to gynecological cancers. Specifically, we tested the hypothesis that downregulation of the Hippo tumor suppressor pathway via loss of core kinases LATS1 and LATS2 could promote ovarian cancer growth via inactivation of pRb and DREAM complex function. We observed that there is a crosstalk between the Hippo pathway and the cell cycle regulatory machinery converging on cyclin D1, a major regulator of CKD4/6 activity. Our observations highlight novel molecular mechanisms that could contribute to cancer pathogenesis and progression.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

8-12-2022

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