Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIPL and MKP-1, thereby antagonizing UV-induced apoptosis
Cyclic AMP inhibits JNK activation by CREB-mediated induction of c-FLIPL and MKP-1, thereby antagonizing UV-induced apoptosis
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DOI：
10.1038/cdd.2008.87
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发表时间：
2008-10-01
影响因子：
12.4
通讯作者：
Lin, A.
中科院分区：
文献类型：
--
作者：
Zhang, J.;Wang, Q.;Lin, A.
环腺苷酸（cAMP）信号通路已被报道促进或抑制细胞凋亡，在细胞环境依赖性的方式。我们以前的研究表明，cAMP，通过蛋白激酶A（PKA）-cAMP反应元件结合蛋白（CREB）-动力蛋白轻链（DLC）途径，负调控丝裂原活化蛋白激酶p38的激活，从而有助于肿瘤坏死因子（TNF）-α诱导的某些类型的细胞凋亡。然而，cAMP如何抑制细胞凋亡在很大程度上仍然是未知的。在此，我们报告cAMP拮抗UV诱导的Rat-1和NIH 3T3细胞凋亡。尽管cAMP显著抑制UV诱导的p38活化，但抑制p38活性对UV诱导的两种细胞系中的细胞死亡均无显著影响。进一步的研究表明，cAMP通过抑制c-Jun N-末端蛋白激酶（JNK）的激活来拮抗UV诱导的细胞凋亡。cAMP介导的JNK激活抑制需要CREB诱导长型细胞FLICE抑制蛋白（c-FLIPL）和促分裂原活化蛋白激酶磷酸酶-1（MKP-1），而不是DLC和p21（WAF 1）。cAMP对UV诱导的细胞凋亡的抑制作用可被c-FLIPL小干扰RNA（siRNA）或MKP-1 siRNA逆转，从而解除cAMP对JNK激活的抑制作用。因此，我们的研究结果提供了一个分子机制，cAMP抑制JNK激活和拮抗细胞凋亡。
The cyclic AMP (cAMP) signaling pathway has been reported to either promote or suppress apoptosis, in a cell context-dependent manner. Our previous study has shown that cAMP, by protein kinase A (PKA)-cAMP response element-binding protein (CREB)-dynein light chain (DLC) pathway, negatively regulates mitogen-activated protein kinase p38 activation, thereby contributing to tumor necrosis factor (TNF)-alpha-induced apoptosis in certain types of cells. However, it remains largely unknown how cAMP suppresses apoptosis. Here we report that cAMP antagonized UV-induced apoptosis in Rat-1 and NIH 3T3 cells. Despite that cAMP significantly suppressed UV-induced p38 activation, inhibition of p38 activity showed no significant effect on UV-induced cell death in both cell lines. Further studies revealed that cAMP antagonized UV-induced apoptosis by inhibition of c-Jun N-terminal protein kinase (JNK) activation. The induction of the long form of cellular FLICE-inhibitory protein (c-FLIPL) and mitogen-activated protein kinase phosphatase-1 (MKP-1), but not DLC and p21(WAF1) by CREB was required for cAMP-mediated inhibition of JNK activation. The suppression by cAMP of UV-induced apoptosis was reversed by c-FLIPL small-interfering RNA (siRNA) or MKP-1 siRNA, which released the inhibition of JNK activation by cAMP. Thus, our results provide a molecular mechanism by which cAMP suppresses JNK activation and antagonizes apoptosis.