Defense Date

2013

Document Type

Thesis

Degree Name

Master of Science

Department

Hematology, Oncology and Palliative Care

First Advisor

Steven Grossman

Abstract

The INK4A-ARF locus encodes two tumor suppressors; p16 and p19Arf, both of which restrain cell growth by regulating the functions of Retinoblastoma (Rb) and p53 respectively. Throughout development, p19Arf is kept at minimal levels, but under conditions of oncogenic stress, p19Arf expression is induced and its tumor suppressive activities are mediated through the stabilization of p53 or in a p53-independent manner. Introducing a point mutation (L46D) into the conserved hydrophobic domain (37-51) in p19Arf annulled ARF/CtBP2 interaction and mediated cell survival by rendering cells irresponsive to apoptosis. In vivo analysis on the percentage of lymphoma free survivals in ARFL46D/L46D mice indicated that disrupting ARF/CtBP2 binding resulted in a tumor spectrum similar to that in ARF-null mice. In this study, we characterized the functions of the hydrophobic domain of ARF in MEF cells under genotoxic stress, ultra-violet irradiation and oncogene activation. We demonstrated that cells bearing the mutation showed decreased responsiveness to H-RasV12 induced senescence consistent with p21 deficiency. We speculate that the deficit in p21 expression is possibly caused by CtBP2 repressive and oncogene -like properties.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2013

Available for download on Sunday, May 13, 2018

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