Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation
Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation
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DOI：
10.1093/emboj/18.23.6845
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发表时间：
1999-12-01
期刊：
影响因子：
11.4
通讯作者：
Fornace, AJ
中科院分区：
文献类型：
--
作者：
Bulavin, DV;Saito, S;Fornace, AJ
ras信号通路的组分有助于细胞p53的活化。在MCF-7细胞中，p38激酶比ras通路的其他成员更有效地活化p53。p53和p38激酶存在于同一物理复合物中，而p38的共表达稳定了p53蛋白。在体外，p38激酶磷酸化p53在Ser 33和Ser 46，一个新发现的位点，这些位点的突变减少p53介导的和UV诱导的细胞凋亡，并且这种减少与UV诱导的Ser 37磷酸化的完全消除和在Ser 33和Ser 46含有丙氨酸的突变体p53中Ser 15磷酸化的显著减少相关，紫外线照射后抑制p38的激活，减少了丝氨酸33，丝氨酸37和丝氨酸15的磷酸化，也显着减少紫外线诱导的细胞凋亡的p53依赖性的方式。这些结果表明，p38激酶在N-末端磷酸化的综合调节中起着重要作用，该磷酸化调节p53介导的UV辐射后的细胞凋亡。
Components of the ras signaling pathway contribute to activation of cellular p53, In MCF-7 cells, p38 kinase activated p53 more effectively than other members of the ras pathway. p53 and p38 kinase exist in the same physical complex, and co-expression of p38 stabilized p53 protein. In vitro, p38 kinase phosphorylated p53 at Ser33 and Ser46, a newly identified site, Mutation of these sites decreased p53-mediated and UV-induced apoptosis, and the reduction correlated with total abrogation of UV-induced phosphorylation on Ser37 and a significant decrease in Ser15 phosphorylation in mutant p53 containing alanine at Ser33 and Ser46, Inhibition of p38 activation after UV irradiation decreased phosphorylation of Ser33, Ser37 and Ser15, and also markedly reduced UV-induced apoptosis in a p53-dependent manner. These results suggest that p38 kinase plays a prominent role in an integrated regulation of N-terminal phosphorylation that regulates p53-mediated apoptosis after UV radiation.