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Phosphorylation of Ser312 contributes to tumor suppression by p53 in vivo
Elizabeth A. Slee, Barbara Benassi, Robert Goldin, Shan Zhong, Indrika Ratnayaka, Giovanni Blandino, Xin Lu and Carol Prives
Proceedings of the National Academy of Sciences of the United States of America
Vol. 107, No. 45 (November 9, 2010), pp. 19479-19484
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/25748699
Page Count: 6
You can always find the topics here!Topics: Tumors, Liver, Lymphoma, Phosphorylation, Insulin resistance, Genetic mutation, Infrared radiation, Embryos, Apoptosis, Irradiation
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The tumor suppressor p53 is a master sensor of stress, and posttranslational modifications are key in controlling its stability and transcriptional activities. p53 can be phosphorylated on at least 23 Ser/Thr residues, the majority of which are phosphorylated by stress-related kinases. An exception is Ser315 in human p53 (Ser312 in mouse), which is predominantly phosphorylated by cell cycle-related kinases. To understand the biological importance of Ser312 phosphorylation in vivo, we generated p53Ser312Ala knock-in mice. We show here that, although Ser312 is not essential for mouse life span under normal physiological conditions, Ser312Ala mutation dampens p53’s activity during embryonic development. This is evident from its partial rescue of embryonic lethality caused by Mdm4 deletion. In agreement with the notion that Ser312 mutation weakens p53 function, Ser312Ala mice are also more susceptible to tumorigenesis following a sublethal ionizing radiation dose. Importantly, in the cohort studied, Ser312 mutation predisposes mice to develop thymic lymphomas and liver tumors, partly due to p53Ser312Ala’s inability to fully induce a set of p53 target genes including p21 and cyclin G1. Thus, we demonstrate that phosphorylation of Ser312 is required for p53 to function fully as a tumor suppressor in vivo.
Proceedings of the National Academy of Sciences of the United States of America © 2010 National Academy of Sciences