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The ataxia telangiectasia-mutated target site Ser18 is required for p53-mediated tumor suppression
Heather L Armata1, David S Garlick, Hayla K Sluss
1Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Abstract:
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.
Insights
Phosphorylation of p53 at Serine 18 by ATM/ATR kinases is crucial for tumor suppression. This ATM/ATR phosphorylation site on p53 contributes to preventing lymphoma and other malignancies in vivo.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- The p53 tumor suppressor protein is regulated by phosphorylation at its N-terminal region.
- Specific sites, like Serine 18 (mouse) and Serine 15 (human), are phosphorylated by ATM and ATR kinases.
- Previous studies suggested this phosphorylation was not essential for p53-mediated tumor suppression.
Purpose of the Study:
- To investigate the role of ATM/ATR-mediated phosphorylation of p53 at Serine 18 in tumor suppression and aging.
- To determine if this specific phosphorylation site is required for preventing spontaneous tumor development.
Main Methods:
- Utilized p53(S18A) mutant mice, where Serine 18 is replaced with Alanine.
- Observed tumor development, survival rates, and aging-associated phenotypes in p53(S18A) mice.
- Analyzed lymphoma development in relation to apoptotic defects and senescence in murine embryonic fibroblasts.
Main Results:
- p53(S18A) mice exhibited compromised survival and developed late-onset lymphomas and other unusual malignancies.
- Lymphoma development in these mice was associated with defects in apoptosis.
- p53(S18A) mice showed early aging phenotypes and their fibroblasts underwent premature senescence.
Conclusions:
- ATM/ATR-mediated phosphorylation of p53 at Serine 18 is essential for effective tumor suppression in vivo.
- This phosphorylation event plays a significant role in preventing the development of lymphomas and other cancers.
- The Serine 18 site on p53 is critical for maintaining genomic stability and preventing premature aging.
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