Laboratory of Molecular Radiooncology, Clinic and Policlinic for Radiation Therapy and Radiooncology, University of Düsseldorf, Düsseldorf, Germany.
Cell Cycle. 2010 Sep 1;9(17):3575-83. doi: 10.4161/cc.9.17.12799. Epub 2010 Sep 25.
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 p38α and glycogen synthase kinase-3 beta (GSK-3β) were found differentially regulated by p21 in a substrate-dependent manner, while casein kinase-1 epsilon (CK1ε) 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.
虽然最初被描述为细胞周期进程的调节剂,但细胞周期蛋白依赖性激酶抑制剂 p21 现在已知还可调节包括转录、分化和凋亡在内的各种其他生物过程。p21 的这些多功能活性主要通过与各种转录因子、促凋亡蛋白和激酶的直接结合来介导,这些蛋白和激酶通常会被这种相互作用抑制。在这里,我们提供了体外证据表明,p21 不仅以显著的底物依赖性方式抑制,而且还以显著的底物依赖性方式激活某些激酶。虽然几种 cJun N 末端激酶 (JNK) 同工型对肿瘤抑制因子 p53 的磷酸化在 p21 存在的情况下大大减弱,但 cJun 的磷酸化仍然不受影响或甚至增强。此外,p21 强烈增加 ERK1 和 ERK2 对 cFos 和 MBP 的磷酸化,而 p53 的磷酸化分别增加和抑制。p38α 和糖原合酶激酶-3β (GSK-3β) 也被发现以底物依赖性方式被 p21 差异调节,而酪蛋白激酶 1 epsilon (CK1ε) 不受影响。结合我们发现 p21 缺陷的 HCT116 结肠癌细胞与 p21 丰富的 HCT116 结肠癌细胞之间应激诱导的 p53 磷酸化模式差异很大,我们的结果表明 p21 能够以负向和正向方式影响激酶活性。