Absence of Wip1 partially rescues Atm deficiency phenotypes in mice

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Wild-type p53-induced phosphatase 1 (WIP1) is a serine/threonine phosphatase that dephosphorylates proteins in the ataxia telangiectasia mutated (ATM)-initiated DNA damage response pathway. WIP1 may have a homeostatic role in ATM signaling by returning the cell to a normal pre-stress state following completion of DNA repair. To better understand the effects of WIP1 on ATM signaling, we crossedAtm-deficient mice toWip1-deficient mice and characterized phenotypes of the double knockout progeny. We hypothesized that the absence of Wip1 might rescue Atm deficiency phenotypes.Atmnull mice, likeATM-deficient humans with the inherited syndrome ataxia telangiectasia, exhibit radiation sensitivity, fertility defects, and are T-cell lymphoma prone. Most double knockout mice were largely protected from lymphoma development and had a greatly extended lifespan compared withAtmnull mice. Double knockout mice had increased p53 and H2AX phosphorylation and p21 expression compared with theirAtmnull counterparts, indicating enhanced p53 and DNA damage responses. Additionally, double knockout splenocytes displayed reduced chromosomal instability compared withAtmnull mice. Finally, doubly null mice were partially rescued from gametogenesis defects observed inAtmnull mice. These results indicate that inhibition of WIP1 may represent a useful strategy for cancer treatment in general and A-T patients in particular.

Oncogene (2012) 31, 1155–1165; doi:10.1038/onc.2011.303; published online 18 July 2011

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