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"Oncogene-Induced Senescence:
Stable or Not?"

by
Priyanka Patel
Interdisciplinary Biomedical Sciences Program
M.S. 2009, University of the Sciences, Philadelphia PA
B.S. 2005, Gujarat University, India


Thesis Advisor: Utz Herbig, Ph.D.
Associate Professor
NJMS-Cancer Center
Department of Microbiology, Biochemistry, & Molecular Genetics

Tuesday, June 28, 2016
10:00 A.M., Cancer Center, G Level Conference Room 1196


Abstract

Oncogene-induced senescence (OIS) is a tumor suppressing mechanism in humans that suppresses cancer progression at pre-malignant stages. Whether this proliferative arrest presents a stable and irreversible barrier to cancer progression, or whether cells can escape this arrest thereby eventually allowing the development of cancer is currently unknown. In this study we demonstrate that cells expressing the oncogenes HRasV12G and BRafV600E undergo a seemingly stable senescence arrest due to formation of dysfunctional telomeres. Following a prolonged period in senescence, however, HRasV12G and BRafV600E expressing cells emerged from growth arrest cultures and continued to proliferate while retaining functional DNA damage responses. Senescence escape was due oncogene-induced chromatin changes that developed over time in senescent cells and that eventually resulted in c-myc dependent derepression of hTERT expression, the catalytic subunit of telomerase. Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated in response to oncogenic signaling. In cells that had escaped OIS, levels of reactivated telomerase activity were similar to those of a number of cancer cell lines and were sufficient to allow anchorage independent growth in the presence of viral oncoproteins. Overall, our data demonstrate that, while initially triggering senescence, persistent MAP kinase signaling eventually leads to escape from OIS due to derepression of hTERT expression. Our data reveal novel insights into the long-term stability of OIS and the mechanisms that cause reactivation of telomerase activity during human cancer development.


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