摘要
    过度活化的聚ADP核糖聚合酶1(PARP-1)能诱导细胞死亡,但目前还未完全了解活化PARP-1的下游信号通路.为了进一步研究PARP-1活化的意义以及聚ADP核糖(PAR)合成在细胞死亡信号途径中的作用,研究人员用DNA烷化剂N-甲基-N′-硝基-N-亚硝基胍(MNNG)处理Hela细胞.结果发现,大量PAR的合成会下调ERK1/2蛋白的磷酸化作用,使Bax蛋白转移到线粒体,并释放细胞色素C和细胞凋亡诱导因子(AIF),随后引起细胞死亡.MNNG及PARP抑制剂PJ34的处理能抑制大剂量PAR的合成,并阻止上述现象的发生,使细胞存活下来.同时,通过抑制MEK对PJ34细胞保护效应的中和,抑制了ERK1/2的磷酸化作用.综上,研究结果证实PARP-1诱导MNNG处理的Hela细胞死亡的过程,在某程度上是通过抑制MEK/ERK信号途径而调节的.而且,PJ34抑制PAR的大量合成能促进ERK1/2的持续活化,起到保护细胞的作用.

PARP-1-induced cell death through inhibition of the MEK/ERK pathway in MNNG-treated HeLa cells
    Poly(ADP-ribose) polymerase-1 (PARP-1) hyper-activation promotes cell death but the signaling events downstream of PARP-1 activation are not fully identified. To gain further information on the implication of PARP-1 activation and PAR synthesis on signaling pathways influencing cell death, we exposed HeLa cells to the DNA alkylating agent N-methyl-N’-methyl-nitro-N-nitrosoguanidine (MNNG). We found that massive PAR synthesis leads to down-regulation of ERK1/2 phosphorylation, Bax translocation to the mitochondria, release of cytochrome c and AIF and subsequently cell death. Inhibition of massive PAR synthesis following MNNG exposure with the PARP inhibitor PJ34 prevented those events leading to cell survival, whereas inhibition of ERK1/2 phosphorylation by inhibiting MEK counteracted the cytoprotective effect of PJ34. Together, our results provide evidence that PARP-1-induced cell death by MNNG exposure in HeLa cells is mediated in part through inhibition of the MEK/ERK signaling pathway and that inhibition of massive PAR synthesis by PJ34, which promotes sustained activation of ERK1/2, leads to cytoprotection.

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