Cancer Susceptibility Polymorphism of p53 at Codon 72 Affects Phosphorylation and Degradation of p53 Protein
Cancer Susceptibility Polymorphism of p53 at Codon 72 Affects Phosphorylation and Degradation of p53 Protein
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DOI：
10.1074/jbc.m110.208587
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发表时间：
2011-05-20
影响因子：
4.8
通讯作者：
Ohki, Rieko
中科院分区：
文献类型：
--
作者：
Ozeki, Chikako;Sawai, Yuichiro;Ohki, Rieko
在过去的20年里，编码脯氨酸或精氨酸的p53密码子72的常见多态性作为与临床结果或癌症风险相关的遗传因素引起了人们的关注。我们现在表明，这两种多态性变体在蛋白质结构上不同，特别是在N-末端区域内，因此，在N末端的翻译后修饰上不同。与脯氨酸形式（p53 - 72 P）相比，精氨酸形式（p53 - 72 R）在Ser-6和Ser-20处显示出显著增强的磷酸化。我们还显示，与p53- 72 P相比，Mdm 2介导的p53 - 72 R降解减少，这至少部分是由于p53- 72 R中Ser-20磷酸化水平较高所致。此外，p53- 72 R表达细胞中p21表达增强，这取决于Ser-6的磷酸化。在激活TGF-β信号传导后，也观察到变体之间的差异p21表达。总的来说，我们证明了一种新的分子差异，同时表明了变异体的肿瘤抑制功能的差异。
The common polymorphism of p53 at codon 72, either encoding proline or arginine, has drawn attention as a genetic factor associated with clinical outcome or cancer risk for the last 2 decades. We now show that these two polymorphic variants differ in protein structure, especially within the N-terminal region and, as a consequence, differ in post-translational modification at the N terminus. The arginine form (p53-72R) shows significantly enhanced phosphorylation at Ser-6 and Ser-20 compared with the proline form (p53-72P). We also show diminished Mdm2-mediated degradation of p53-72R compared with p53-72P, which is at least partly brought about by higher levels of phosphorylation at Ser-20 in p53-72R. Furthermore, enhanced p21 expression in p53-72R-expressing cells, which is dependent on phosphorylation at Ser-6, was demonstrated. Differential p21 expression between the variants was also observed upon activation of TGF-beta signaling. Collectively, we demonstrate a novel molecular difference and simultaneously suggest a difference in the tumor-suppressing function of the variants.