Date on Master's Thesis/Doctoral Dissertation

12-2015

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Biochemistry and Molecular Biology

Degree Program

Biochemistry and Molecular Biology, PhD

Committee Chair

Clark, Geoffrey J.

Committee Co-Chair (if applicable)

Donninger, Howard

Committee Member

Donninger, Howard

Committee Member

Cole, Marsha P.

Committee Member

Schaner Tooley, Christine

Committee Member

Samuelson, David

Author's Keywords

Ras; NORE1A; retinoblastoma protein; phosphoprotein phosphatase 1; senescence; tumor suppressor gene

Abstract

Ras is the most frequently mutated oncogene in human cancers. It acts as a critical branch point in signal transduction, regulating numerous downstream effectors involved in cell growth and differentiation. While Ras can activate many growth promoting pathways, it can paradoxically regulate growth inhibitory pathways leading to apoptosis and cell cycle arrest. One of the ways Ras can inhibit the growth of cells is via a family of effectors called the RASSF proteins. RASSF5 (NORE1A) is a tumor suppressor that is frequently inactivated in human tumors by epigenetic mechanisms. NORE1A binds directly to Ras and promotes Ras-induced senescence. We have recently shown in the laboratory that NORE1A serves as a senescence effector of Ras by activating the p53 tumor suppressor. However, knockdown of p53 did not completely abrogate the ability of NORE1A to induce senescence, suggesting that there may be additional mechanisms by which NORE1A promotes senescence. The other pathway involved in Ras-induced senescence is the Rb pathway. We show that NORE1A forms an endogenous, Ras regulated complex with the Rb phosphatase PP1A. Furthermore, our results show that NORE1A scaffolds PP1A to Rb in a Ras dependent manner, in turn promoting the dephosphorylation of Rb, a pro-senescent event. We found that NORE1A can also regulate the acetylation and SUMOylation of Rb, and that loss of Rb significantly suppressed the ability of NORE1A to induce senescence. Collectively, our work strongly suggests that NORE1A is a double barreled Ras senescence node, explaining why Ras driven tumors often show loss of NORE1A expression.

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