The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression.
The p53 tumor suppressor is phosphorylated at multiple sites within its NH(2)-terminal region. One of these phosphorylation sites (mouse Ser(18) and human Ser(15)) 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 Ser(18) with Ala) have indicated that ATM/ATR phosphorylation of p53 Ser(18) 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 Ser(18) 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 Ser(18) on p53 contributes to tumor suppression in vivo.
Armata
Heather L
HL
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Garlick
David S
DS
Sluss
Hayla K
HK
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002455:Cell Division; D016922:Cellular Senescence; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005838:Genotype; D018095:Germ-Line Mutation; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000517:prevention & control; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012694:Serine; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D012694:Serine; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases