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The Ataxia Telangiectasia–Mutated Target Site Ser¹⁸ Is Required for p53-Mediated Tumor Suppression

¹ Department of Cancer Biology, University of Massachusetts Medical School and ² Charles River Laboratories, Worcester, Massachusetts

Requests for reprints: Hayla K. Sluss, Department of Cancer Biology, LRB 370W, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01655. Phone: 508-856-3372; Fax: 508-856-6797; E-mail: hayla.sluss{at}umassmed.edu.

The p53 tumor suppressor is phosphorylated at multiple sites within its NH₂-terminal region. One of these phosphorylation sites (mouse Ser¹⁸ and human Ser¹⁵) is a substrate for the ataxia telangiectasia–mutated (ATM) and ATM-related (ATR) protein kinases. Studies of p53^S18A mice (with a germ-line mutation that replaces Ser¹⁸ with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser¹⁸ is required for normal DNA damage–induced PUMA expression and apoptosis but not for DNA damage–induced cell cycle arrest. Unlike p53-null mice, p53^S18A mice did not succumb to early-onset tumors. This finding suggested that phosphorylation of p53 Ser¹⁸ was not required for p53-dependent tumor suppression. Here we report that the survival of p53^S18A mice was compromised and that they spontaneously developed late-onset lymphomas (between ages 1 and 2 years). These mice also developed several malignancies, including fibrosarcoma, leukemia, leiomyosarcoma, and myxosarcoma, which are unusual in p53 mutant mice. Furthermore, we found that lymphoma development was linked with apoptotic defects. In addition, p53^S18A animals exhibited several aging-associated phenotypes early, and murine embryonic fibroblasts from these animals underwent early senescence in culture. Together, these data indicate that the ATM/ATR phosphorylation site Ser¹⁸ on p53 contributes to tumor suppression in vivo. [Cancer Res 2007;67(24):11696–703]

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				Correction: Tumor Analysis of p53S18A Mice Cancer Res., June 1, 2008; 68(11): 4486 - 4486. [Full Text] [PDF]