Zhang Jiyan, Bui Truc N, Xiang Jialing, Lin Anning
Ben May Institute for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
Mol Cell Biol. 2006 Feb;26(4):1223-34. doi: 10.1128/MCB.26.4.1223-1234.2006.
The mitogen-activated protein kinase p38 plays a critical role in inflammation, cell cycle progression, differentiation, and apoptosis. The activity of p38 is stimulated by a variety of extracellular stimuli, such as the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha), and subjected to regulation by other intracellular signaling pathways, including the cyclic AMP (cAMP) pathway. Yet the underlying mechanism by which cAMP inhibits p38 activation is unknown. Here we show that the induction of dynein light chain (DLC) by cAMP response element-binding protein (CREB) is required for cAMP-mediated inhibition of p38 activation. cAMP inhibits p38 activation via the protein kinase A-CREB pathway. The inhibition is mediated by the CREB target gene Dlc, whose protein product, DLC, interferes with the formation of the MKK3/6-p38 complex, thereby suppressing p38 phosphorylation activation by MKK3/6. The inhibition of p38 activation by cAMP leads to suppression of NF-kappaB activity and promotion of apoptosis in response to TNF-alpha. Thus, our results identify DLC as a novel inhibitor of the p38 pathway and provide a molecular mechanism by which cAMP suppresses p38 activation and promotes apoptosis.
丝裂原活化蛋白激酶p38在炎症、细胞周期进程、分化和细胞凋亡中起关键作用。p38的活性受到多种细胞外刺激的激发，如促炎细胞因子肿瘤坏死因子α（TNF-α），并受到包括环磷酸腺苷（cAMP）途径在内的其他细胞内信号通路的调节。然而，cAMP抑制p38激活的潜在机制尚不清楚。在这里，我们表明，cAMP反应元件结合蛋白（CREB）诱导动力蛋白轻链（DLC）是cAMP介导的抑制p38激活所必需的。cAMP通过蛋白激酶A-CREB途径抑制p38激活。这种抑制是由CREB靶基因Dlc介导的，其蛋白产物DLC干扰MKK3/6-p38复合物的形成，从而抑制MKK3/6对p38的磷酸化激活。cAMP对p38激活的抑制导致NF-κB活性的抑制和对TNF-α诱导的细胞凋亡的促进。因此，我们的结果确定DLC是p38途径的一种新型抑制剂，并提供了一种分子机制，通过该机制cAMP抑制p38激活并促进细胞凋亡。
