Phosphorylation at the carboxyl terminal S373 and S375 residues and 14-3-3 binding are not required for mouse p53 function

Ming Kei Lee and Kanaga Sabapathy

Year 2007, Volume 9, Issue 9

Abstract

g-irradiation-mediated, ATM-dependent dephosphorylation of serine 376 (S376) at the carboxyl-terminus of human p53 results in the exposure of the 14-3-3 consensus binding site, which includes S378. 14-3-3 binding potentiates p53’s DNA-binding ability and causes a G1 arrest. Moreover, endoplasmic reticulum (ER) stress-mediated S376 phosphorylation was shown to localize human p53 in the cytoplasm. Though many functions are conserved between human and mouse p53, the functional relevance of the S376 and S378 mouse equivalent is not clear. We report here that g-irradiation does not lead to 14-3-3 binding to mouse p53. Mouse p53 mutants, such as S373A/D (the equivalent of human S376), S375A/D (the equivalent of human S378) and combinatorial double mutants, were not impaired in their ability to transactivate p53-dependent target genes, and were capable of inducing G1 arrest as efficiently as wild-type p53. Consistently, all mutant p53s were as potent as wild-type mouse p53 in inhibiting cellular colony formation. Furthermore, mouse S373A/D mutants were not defective in cytoplasmic localization in response to ER stress. Together, the data suggests that despite the high homology with human p53, neither the phosphorylation status at S373 and S375 nor 14-3-3 binding may be critical events for mouse p53 to be functional.

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