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J. Biol. Chem., Vol. 282, Issue 43, 31398-31408, October 26, 2007

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p38 Antagonizes p38 Activity through c-Jun-dependent Ubiquitin-proteasome Pathways in Regulating Ras Transformation and Stress Response^*

Xiaomei Qi¹, Nicole M. Pohl¹, Mathew Loesch, Songwang Hou, Rongshan Li, Jian-Zhong Qin^¶, Ana Cuenda^||, and Guan Chen^**2

From the Department of Pharmacology and Toxicology, ^**Zablocki Department of Veterans Affairs Medical Center, and Department of Pathology, Medical College of Wisconsin, Wisconsin 53226, ^¶Cancer Center and Department of Pathology, Loyola University Chicago, Maywood, Illinois 60153, and ^||MRC Protein Phosphorylation Unit, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom

p38 MAPK family consists of four isoform proteins (, , , and ) that are activated by the same stimuli, but the information about how these proteins act together to yield a biological response is missing. Here we show a feed-forward mechanism by which p38 may regulate Ras transformation and stress response through depleting its family member p38 protein via c-Jun-dependent ubiquitin-proteasome pathways. Analyses of MAPK kinase 6 (MKK6)-p38 fusion proteins showed that constitutively active p38 (MKK6-p38) and p38 (MKK6-p38) stimulates and inhibits c-Jun phosphorylation respectively, leading to a distinct AP-1 regulation. Depending on cell type and/or stimuli, p38 phosphorylation results in either Ras-transformation inhibition or a cell-death escalation that invariably couples with a decrease in p38 protein expression. p38, on the other hand, increases Ras-dependent growth or inhibits stress induced cell-death independent of phosphorylation. In cells expressing both proteins, p38 phosphorylation decreases p38 protein expression, whereas its inhibition increases cellular p38 concentrations, indicating an active role of p38 phosphorylation in negatively regulating p38 protein expression. Mechanistic analyses show that p38 requires c-Jun activation to deplete p38 proteins by ubiquitin-proteasome pathways. These results suggest that p38 may, upon phosphorylation, act as a gatekeeper of the p38 MAPK family to yield a coordinative biological response through disrupting its antagonistic p38 family protein.

Received for publication, May 10, 2007 , and in revised form, August 20, 2007.

^* This work was supported by NCI, National Institutes of Health Grant 2R01 CA91576 and grants from the Department of Veterans Affairs (Merit Review), the Charlotte Geyer Foundation, and Advancing a Healthier Wisconsin fund (to G. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. Tel.: 414-456-8636; Fax: 414-456-6545; E-mail: gchen{at}mcw.edu.

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