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Molecular and Cellular Biology, January 2007, p. 510-517, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01355-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

MEKK1 Mediates the Ubiquitination and Degradation of c-Jun in Response to Osmotic Stress{triangledown}

Yan Xia,1 Ji Wang,2 Shuichan Xu,3 Gary L. Johnson,4 Tony Hunter,5 and Zhimin Lu1,6,7*

Brain Tumor Center and Department of Neuro-Oncology,1 Department of Thoracic and Cardiovascular Surgery,2 Department of Molecular Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,6 Signal Pharmaceuticals, LLC, San Diego, California 92121,3 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599,4 Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037,5 The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas 770307

Received 24 July 2006/ Returned for modification 22 September 2006/ Accepted 25 October 2006

c-Jun, a major transcription factor in the activating protein 1 family of regulatory proteins, is activated by many physiologic and pathological stimuli. We show here that c-Jun was downregulated in response to osmotic stress via ubiquitination-dependent degradation by the PHD/RING finger domain of MEKK1, which exhibited E3 ubiquitin ligase activity toward c-Jun in vitro and in vivo. The reduced c-Jun protein level resulting from exogenous expression of wild-type MEKK1 and the opposite effect induced by expression of a MEKK1 PHD/RING finger domain mutant were consistent with a higher level of c-Jun protein in MEKK1–/– cells than in corresponding wild-type cells. The deficiency of MEKK1 blocked posttranslational downregulation of c-Jun in response to osmotic stress. Furthermore, apoptosis induced by osmotic stress was suppressed by overexpression of c-Jun, indicating that the downregulation of c-Jun promotes apoptosis.

* Corresponding author. Mailing address: Department of Neuro-Oncology, Unit 1002, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 834-6231. Fax: (713) 834-6230. E-mail: zhiminlu{at}mdanderson.org.

{triangledown} Published ahead of print on 13 November 2006.

Molecular and Cellular Biology, January 2007, p. 510-517, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.01355-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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