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Molecular and Cellular Biology, October 2007, p. 6933-6947, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.02385-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Regulation of Mucin Gene Expression by CREB via a Nonclassical Retinoic Acid Signaling Pathway{triangledown}

Seung-Wook Kim,1 Jeong Soo Hong,1 Seung-Hee Ryu,1 Wen-Cheng Chung,1 Joo-Heon Yoon,2 and Ja Seok Koo1,3*

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030,1 Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul 120-752, South Korea,2 Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas3

Received 20 December 2006/ Returned for modification 26 February 2007/ Accepted 9 July 2007

Vitamin A and its metabolite retinoic acid (RA) are essential elements for normal lung development and the differentiation of lung epithelial cells. We previously showed that RA rapidly activated cyclic AMP response element-binding protein (CREB) in a nonclassical manner in normal human tracheobronchial epithelial (NHTBE) cells. In the present study, we further demonstrated that this nonclassical signaling of RA on the activation of CREB plays a critical role in regulating the expression of airway epithelial cell differentiation markers, the MUC2, MUC5AC, and MUC5B genes. We found that RA rapidly activates the protein kinase C{alpha} isozyme and transmits the activation signal to CREB via the Raf/MEK/extracellular signal-regulated kinase/p90 ribosomal S6 kinase (RSK) pathway. Activated RSK translocated from the cytoplasm to the nucleus, where it phosphorylates CREB. Activated CREB then binds to a cis-acting replication element motif on the promoter (at nucleotides [nt] –878 to –871) of the MUC5AC gene. The depletion of CREB using small interfering RNA abolished not only the RA-induced MUC5AC but also RA-induced MUC2 and MUC5B. Taken together, our findings demonstrate that CREB activation via this nonclassical RA signaling pathway may play an important role in regulating the expression of mucin genes and mediating the early biological effects of RA during normal mucous differentiation in NHTBE cells.

* Corresponding author. Mailing address: Department of Thoracic/Head and Neck Medical Oncology, Unit 432, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-8454. Fax: (713) 794-5997. E-mail: jskoo{at}mdanderson.org

{triangledown} Published ahead of print on 23 July 2007.

Molecular and Cellular Biology, October 2007, p. 6933-6947, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.02385-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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