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Molecular and Cellular Biology, February 2005, p. 1054-1069, Vol. 25, No. 3
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.3.1054-1069.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

c-Jun N-Terminal Kinase Contributes to Aberrant Retinoid Signaling in Lung Cancer Cells by Phosphorylating and Inducing Proteasomal Degradation of Retinoic Acid Receptor {alpha}

Harish Srinivas,1 Denise M. Juroske,1 Shailaja Kalyankrishna,1 Dianna D. Cody,2 Roger E. Price,2 Xiao-Chun Xu,3 Ramesh Narayanan,4 Nancy L. Weigel,4 and Jonathan M. Kurie1*

Departments of Thoracic/Head and Neck Medical Oncology,1 Imaging Physics,2 Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center,3 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas4

Received 5 June 2004/ Returned for modification 30 July 2004/ Accepted 25 October 2004

Retinoic acid (RA) is the ligand for nuclear RA receptors (RARs and RXRs) and is crucial for normal epithelial cell growth and differentiation. During malignant transformation, human bronchial epithelial cells acquire a block in retinoid signaling caused in part by a transcriptional defect in RARs. Here, we show that activation of c-Jun N-terminal kinase (JNK) contributes to RAR dysfunction by phosphorylating RAR{alpha} and inducing degradation through the ubiquitin-proteasomal pathway. Analysis of RAR{alpha} mutants and phosphopeptide mapping revealed that RAR{alpha} residues Thr181, Ser445, and Ser461 are phosphorylated by JNK. Mutation of these residues to alanines prevented efficient ubiquitination of RAR{alpha} and increased the stability of the protein. We investigated the importance of RAR{alpha} phosphorylation by JNK as a mediator of retinoid resistance in lung cancer. Mice that develop lung cancer from activation of a latent K-ras oncogene had high intratumoral JNK activity and low RAR{alpha} levels and were resistant to treatment with an RAR ligand. JNK inhibition in a human lung cancer cell line enhanced RAR{alpha} levels, ligand-induced activity of RXR-RAR dimers, and growth inhibition by RA. These findings point to JNK as a key mediator of aberrant retinoid signaling in lung cancer cells.

* Corresponding author. Mailing address: Department of Thoracic/Head and Neck Oncology—Unit 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 792-6363. Fax: (713) 796-8655. E-mail: jkurie{at}mdanderson.org.

Molecular and Cellular Biology, February 2005, p. 1054-1069, Vol. 25, No. 3
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.3.1054-1069.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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