MCB Accepts, published online ahead of print on 23 July 2007

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Mol. Cell. Biol. doi:10.1128/MCB.02385-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Regulation of Mucin Gene Expression by CREB via a Nonclassical RA Signaling Pathway

Seung-Wook Kim, Jeong Soo Hong, Seung-Hee Ryu, Wen-Cheng Chung, Joo-Heon Yoon, and Ja Seok Koo^*

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

^* To whom correspondence should be addressed. Email: jskoo{at}mdanderson.org.

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 cAMP 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, MUC2, MUC5AC, and MUC5B genes. We found that RA rapidly activates the protein kinase C (PKC) isozyme and transmits the activation signal to CREB via the Raf/MEK/ERK/RSK pathway. Activated RSK translocated from the cytoplasm to the nucleus, where it phosphorylates CREB. Activated CREB then binds to a CRE motif on the promoter (at nucleotides -878 to -871) of MUC5AC gene. 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 expression of mucin genes and mediating the early biological effects of RA during normal mucous differentiation in NHTBE cells.

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