Cyclic AMP Inhibits p38 Activation via CREB-Induced Dynein Light Chain

Abstract

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-α), 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-κB activity and promotion of apoptosis in response to TNF-α. 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.

We are grateful to Chen-Ming Fan, Jiahuai Han, Stanley Korsmeyer, Marc Montminy, Wei-Jen Tang, and Zhenguo Wu for providing reagents that make this work possible and Zhenguo Wu for helpful discussion.

This work was partially supported by National Institutes of Health grants CA92650 and CA100460 (to A.L.).