Induction of WAF1/CIP1 by a p53-independent pathway.
Induction of WAF1/CIP1 by a p53-independent pathway.
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发表时间：
1994-07
期刊：
影响因子：
11.2
通讯作者：
P. Michieli;M. Chedid;D. Lin;J. Pierce;Mercer We;D. Givol
中科院分区：
文献类型：
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作者：
P. Michieli;M. Chedid;D. Lin;J. Pierce;Mercer We;D. Givol
P53诱导基因WAF1/CIP1编码一个M(R)21,000蛋白(P21)，已被证明通过抑制细胞周期蛋白依赖的激酶来阻止细胞生长。WAF1/CIP1在经历P53依赖的G1期停滞或凋亡的细胞中的诱导支持WAF1/CIP1是P53的关键下游效应因子的观点。在本研究中，我们使用P53“敲除”小鼠的胚胎成纤维细胞来证明WAF1/CIP1的诱导不依赖于P53。我们发现，血清或个别生长因子，如血小板衍生生长因子、成纤维细胞生长因子和表皮生长因子，而不是胰岛素，能够在静止的P53缺陷细胞和正常细胞中诱导WAF1/CIP1。这种瞬时诱导的动力学被放线菌亚胺增强，表明WAF1/CIP1是一个即刻早期基因，其转录在血清或生长因子刺激后约2小时达到峰值。另一方面，辐射诱发的DNA损伤可诱导正常人和小鼠成纤维细胞中WAF1/CIP1的表达，但不影响P53缺陷细胞中WAF1/CIP1的表达。这些结果表明，WAF1/CIP1的诱导存在两条不同的途径，一条是由DNA损伤激活的依赖于P53的途径，另一条是在进入细胞周期时由有丝分裂原激活的非依赖于P53的途径。对p21在早期阶段的可能功能进行了讨论。
The p53-inducible gene WAF1/CIP1 encodes a M(r) 21,000 protein (p21) that has been shown to arrest cell growth by inhibition of cyclin-dependent kinases. Induction of WAF1/CIP1 in cells undergoing p53-dependent G1 arrest or apoptosis supports the idea that WAF1/CIP1 is a critical downstream effector of p53. In the present study, we used embryonic fibroblasts from p53 "knock-out" mice to demonstrate p53-independent induction of WAF1/CIP1. We show that serum or individual growth factors such as platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor but not insulin are able to induce WAF1/CIP1 in quiescent p53-deficient cells as well as in normal cells. The kinetics of this transient induction, which is enhanced by cycloheximide, demonstrates that WAF1/CIP1 is an immediate-early gene the transcript of which reaches a peak at approximately 2 h following serum or growth factor stimulation. On the other hand, DNA damage elicited by gamma-irradiation induces WAF1/CIP1 in normal human and mouse fibroblasts but does not affect WAF1/CIP1 expression in p53-deficient cells. These results suggest the existence of two separate pathways for the induction of WAF1/CIP1, a p53-dependent one activated by DNA damage and a p53-independent one activated by mitogens at the entry into the cell cycle. The possible function of p21 at this early stage is discussed.