Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress
Jun NH2-terminal kinase phosphorylation of p53 on Thr-81 is important for p53 stabilization and transcriptional activities in response to stress
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DOI：
10.1128/mcb.21.8.2743-2754.2001
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发表时间：
2001-04-01
影响因子：
5.3
通讯作者：
Ronai, Z
中科院分区：
文献类型：
--
作者：
Buschmann, T;Potapova, O;Ronai, Z
p53肿瘤抑制蛋白在应激介导的生长停滞和细胞凋亡的调节中发挥关键作用。应激诱导的p53磷酸化密切调节其稳定性和转录活性。质谱分析293 T细胞中通过活性Jun NH 2-末端激酶（JNK）磷酸化的p53，鉴定T81为JNK磷酸化位点。JNK磷酸化p53在T81响应DNA损伤和应激诱导剂，如T81的磷酸化特异性抗体所确定的。与野生型p53不同，在JNK刺激下，T81上突变的p53（T81 A）没有表现出增加的表达或伴随的转录活性激活、生长抑制、酸性凋亡。在表达JNK激酶的细胞中，JNK磷酸酶MKP 5的强制表达降低了T81磷酸化，同时降低了p53转录活性和p53介导的凋亡。类似地，反义JNK 1和-2的转染降低了响应于UV照射的T81磷酸化。据报道，超过180种人类肿瘤含有在包含T81和JNK结合位点（氨基酸81至116）的区域内具有突变的p53。我们的研究确定了一个额外的机制，调节p53的稳定性和功能活动，以应对压力。
The p53 tumor suppressor protein plays a key role in the regulation of stress-mediated growth arrest and apoptosis. Stress-induced phosphorylation of p53 tightly regulates its stability and transcriptional activities. Mass spectrometry analysis of p53 phosphorylated in 293T cells by active Jun NH2-terminal kinase (JNK) identified T81 as the JNK phosphorylation site. JNK phosphorylated p53 at T81 in response to DNA damage and stress-inducing agents, as determined by phospho-specific antibodies to T81. Unlike wild-type p53, in response to JNK stimuli p53 mutated on T81 (T81A) did not exhibit increased expression or concomitant activation of transcriptional activity, growth inhibition, acid apoptosis, Forced expression of MKP5, a JNK phosphatase, in JNK kinase-expressinig cells decreased T81 phosphorylation while reducing p53 transcriptional activity and p53-mediated apoptosis. Similarly transfection of antisense JNK 1 and -2 decreased T81 phosphorylation in response to UV irradiation. More than 180 human tumors have been reported to contain p53 with mutations within the region that encompasses T81 and the JNK binding site (amino acids 81 to 116). Our studies identify an additional mechanism for the regulation of p53 stability and functional activities in response to stress.