Evidence for a differential modulation of p53-phosphorylating kinases by the cyclin-dependent kinase inhibitor p21WAF1/CIP1
Evidence for a differential modulation of p53-phosphorylating kinases by the cyclin-dependent kinase inhibitor p21WAF1/CIP1
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DOI：
10.4161/cc.9.17.12799
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发表时间：
2010-09-01
期刊：
影响因子：
4.3
通讯作者：
Jaenicke, Reiner U.
中科院分区：
文献类型：
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作者：
Neise, Denise;Sohn, Dennis;Jaenicke, Reiner U.
虽然最初被描述为细胞周期进程的调节剂，但现在已知细胞周期蛋白依赖性激酶抑制剂p21也调节各种其他生物过程，包括转录、分化和凋亡。p21的这些多功能活性主要通过直接结合到通常被这种相互作用抑制的各种转录因子、促凋亡蛋白和激酶来介导。在这里，我们提供了在体外的证据表明，p21不仅抑制，但也激活某些激酶在一个显着的底物依赖性的方式。而磷酸化的肿瘤抑制p53的cJun N-末端激酶（JNK）的几种亚型的p21的存在下大大减弱，磷酸化的cJun保持不受影响，甚至增强。此外，p21强烈增加ERK 1和ERK 2对cFos和MBP的磷酸化，而p53磷酸化分别增加和抑制。此外，p38 α和糖原合成酶激酶-3 β（GSK-3 β）被发现以底物依赖性方式受到p21的差异调节，而酪蛋白激酶-1 β（CK 1 β）不受影响。再加上我们的发现，压力诱导的p53磷酸化模式有很大的不同p21-精通和缺陷的HCT 116结肠癌细胞，我们的研究结果表明，p21是能够影响激酶的活动，无论是在一个积极的和消极的方式。
Although initially described as a regulator of cell cycle progression, the cyclin-dependent kinase inhibitor p21 is now known to also modulate various other biological processes including transcription, differentiation and apoptosis. These versatile activities of p21 are mainly mediated via direct binding to various transcription factors, pro-apoptotic proteins and kinases that are usually inhibited by this interaction. Here we provide in vitro evidence that p21 not only inhibits, but also activates certain kinases in a remarkable substrate-dependent manner. Whereas phosphorylation of the tumor suppressor p53 by several isoforms of the cJun N-terminal kinases (JNKs) was greatly attenuated in the presence of p21, phosphorylation of cJun remained either unaffected or was even enhanced. Furthermore, p21 strongly increased phosphorylation of cFos and MBP by ERK1 and ERK2, while p53 phosphorylation was increased and inhibited, respectively. Also p38 alpha and glycogen synthase kinase-3 beta (GSK-3 beta) were found differentially regulated by p21 in a substrate-dependent manner, while casein kinase-1 epsilon (CK1 epsilon) was not affected. Together with our finding that the stress-induced p53 phosphorylation pattern differs greatly between p21-proficient and -deficient HCT116 colon carcinoma cells, our results suggest that p21 is able to influence kinase activities both in a negative and positive manner.