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Regulation of p53 Function and Stability by Phosphorylation

机译：磷酸化对p53功能和稳定性的调节

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The p53 tumor suppressor protein can be phosphorylated at several sites within the N- and C-terminal domains, and several protein kinases have been shown to phosphorylate p53 in vitro. In this study, we examined the activity of p53 proteins with combined mutations at all of the reported N-terminal phosphorylation sites (p53N-term), all of the C-terminal phosphorylation sites (p53C-term), or all of the phosphorylation sites together (p53N/C-term). Each of these mutant proteins retained transcriptional transactivation functions, indicating that phosphorylation is not essential for this activity of p53, although a subtle contribution of the C-terminal phosphorylation sites to the activation of expression of the endogenous p21Waf1/Cip1-encoding gene was detected. Mutation of the phosphorylation sites to alanine did not affect the sensitivity of p53 to binding to or degradation by Mdm2, although alteration of residues 15 and 37 to aspartic acid, which could mimic phosphorylation, resulted in a slight resistance to Mdm2-mediated degradation, consistent with recent reports that phosphorylation at these sites inhibits the p53-Mdm2 interaction. However, expression of the phosphorylation site mutant proteins in both wild-type p53-expressing and p53-null lines showed that all of the mutant proteins retained the ability to be stabilized following DNA damage. This indicates that phosphorylation is not essential for DNA damage-induced stabilization of p53, although phosphorylation could clearly contribute to p53 stabilization under some conditions.
机译：p53肿瘤抑制蛋白可以在N和C端结构域的多个位点被磷酸化，并且几种蛋白激酶已经显示出可以在体外磷酸化p53。在这项研究中，我们检查了在所有报道的N末端磷酸化位点（p53N-term），所有C末端磷酸化位点（p53C-term）或所有磷酸化位点具有组合突变的p53蛋白的活性。 （p53N / C项）。尽管C端磷酸化位点对内源性p21 Waf1 / Cip1表达激活的微弱贡献，但这些突变蛋白均保留了转录反式激活功能，这表明磷酸化对于p53的活性不是必需的。检测到编码sup>的基因。磷酸化位点向丙氨酸的突变不会影响p53与Mdm2结合或降解的敏感性，尽管残基15和37对天冬氨酸的改变（可以模仿磷酸化作用）导致对Mdm2介导的降解略有抵抗力，这是一致的最近的报道表明，这些位点的磷酸化抑制了p53-Mdm2的相互作用。但是，磷酸化位点突变蛋白在野生型p53表达和p53无蛋白系中的表达表明，所有突变蛋白都保留了DNA损伤后稳定的能力。这表明磷酸化对于DNA损伤诱导的p53稳定化不是必不可少的，尽管在某些条件下磷酸化显然可以促进p53稳定化。

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