Wild-type p53-induced phosphatase 1 (Wip1) regulates cellular senescence in Mouse Embryonic Fibroblasts through p53-dependent and –independent pathways

Tuesday, October 09, 2012 — Poster Session I
1:00 p.m. – 3:00 p.m	Natcher Conference Center, Building 45	NCI	AGING-8

Authors

• H. Sakai
• C.E. Redon
• K. Ishida
• W.M. Bonner
• E. Appella
• S. Mazur

Abstract

Wip1 is a nuclear serine/threonine phosphatase that is induced by p53 following activation of the DNA damage response (DDR). Upon repair of damage, Wip1 phosphatase activity dampens stress signaling and facilitates the return to homeostasis, thus, regulating recovery from DDR activation. Wip1 is frequently overexpressed in human tumors. Interestingly, although Wip1 knockout mice are resistant to tumorigenesis, they exhibit reproductive and immune system defects, increased stress sensitivity and a moderately reduced lifespan. Under conventional culture conditions, Wip1-/- mouse embryonic fibroblasts (MEFs) undergo premature senescence. We have investigated the mechanism by which Wip1 reduces premature senescence in MEFs. We found that reduced oxygen pressure only partially suppressed premature senescence. Compared with the corresponding Wild-type cells, early passage Wip1-/- MEFs under both 20% and 3% oxygen conditions exhibited increased activation of p53 and increased levels of p21, p16Ink4a and p19Arf. Furthermore, we found that the increased level of γ-H2AX found in Wip1-/- MEFs was specifically associated with cells in S-phase, suggesting that replicative stress activated the DDR. The absence of p38 MAPK activation implies that Wip1 may regulate transcription of the Ink4a/Arf locus through a novel pathway. These findings suggest that Wip1 prevents cellular senescence by regulating both DDR and p16Ink4a/p19Arf signaling.

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