Defining the functions of a conserved hydrophobic domain in the ARF tumor suppressor

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.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

Thesis

Discipline thesis:degree_discipline

Hematology, Oncology and Palliative Care

Year dc:date.available

2013

Author dc:creator

• Hariz, Aymen

Contributors dc:contributor

• Steven Grossman

• Defense

Statement dc:rights

• © The Author

Identifier

https://scholarscompass.vcu.edu/etd/481

OAI identifier oai:identifier

oai:scholarscompass.vcu.edu:etd-1480