Date on Master's Thesis/Doctoral Dissertation

8-2016

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)

Gregg, Ronald G.

Committee Member

Gregg, Ronald G.

Committee Member

Klinge, Carolyn M.

Committee Member

Mitchell, Robert A.

Committee Member

Tooley, Christine Schaner

Author's Keywords

Ras; NORE1A; PML; cancer; tumor suppressor

Abstract

Ras is the most commonly activated oncogene in human cancer. Activated Ras drives cell growth and proliferation by activating multiple mitogenic signaling pathways. However, Ras also has the paradoxical ability to promote anti-growth, pro-apoptotic, and pro-senescent signaling. The signaling pathways of many of these biological effectors remain poorly defined. One group of proteins capable of promoting Ras-induced apoptosis and cell cycle arrest is the RASSF family of tumor suppressors. Novel Ras Effector 1A, or NORE1A, was the first member of this family discovered and is a bona fide tumor suppressor that is lost or inactivated in a number of different cancers. NORE1A promotes anti-growth properties of Ras and has recently been shown to act as a double barreled Ras senescence effector, driving Ras-induced senescence, or cell cycle arrest, by activating two major tumor suppressors, p53 and Rb. NORE1A interacts with proteins that promote post-translational modifications of p53 and Rb in small nuclear spots, and NORE1A alone also forms small dots in the nucleus. NORE1A’s localization in the nucleus has not been extensively studied, but the most famous protein that forms spots in the nucleus, referred to as nuclear bodies, is the Promyelocytic Leukemia protein, or PML. PML nuclear bodies are centers of protein regulation and post-translational modifications, and PML itself is a tumor suppressor that can be lost in certain cancers. PML is a critical component of Ras-induced senescence, and upon stimulation by activated Ras, PML nuclear bodies mediate the activation and post-translational modifications of p53 and Rb, but the exact coordination of this process is unknown. Here, I show that NORE1A localizes to PML nuclear bodies and forms a novel, Ras-enhanced association with a specific isoform of PML, PMLIV. NORE1A promotes the recruitment of the senescence effectors p53 and Rb to PMLIV nuclear bodies. Moreover, the loss of PML expression prevents NORE1A from inducing senescence. Thus, NORE1A requires localization to PML, and specifically PMLIV, nuclear bodies to mediate its pro-senescent effects by promoting the localization of p53 and Rb to PMLIV, revealing a novel component of the PMLIV/Ras senescence signaling pathway.

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