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Molecular and Cellular Biology, February 2006, p. 1223-1234, Vol. 26, No. 4
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.4.1223-1234.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Jiyan Zhang,1 Truc N. Bui,1 Jialing Xiang,2 and Anning Lin1*

Ben May Institute for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637,1 Department of Biological, Chemical, and Physical Science, Illinois Institute of Technology, 3101 South Dearborn Street, Chicago, Illinois 606162

Received 19 August 2005/ Returned for modification 19 September 2005/ Accepted 2 December 2005

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-{kappa}B 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.

* Corresponding author. Mailing address: Ben May Institute for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, IL 60637. Phone: (773) 753-1408. Fax: (773) 702-6260. E-mail: alin{at}huggins.bsd.uchicago.edu.

Molecular and Cellular Biology, February 2006, p. 1223-1234, Vol. 26, No. 4
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.4.1223-1234.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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