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Originally published In Press as doi:10.1074/jbc.M200353200 on June 20, 2002

J. Biol. Chem., Vol. 277, Issue 36, 32624-32631, September 6, 2002
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Phorbol 12-Myristate 13-Acetate Up-regulates the Transcription of MUC2 Intestinal Mucin via Ras, ERK, and NF-kappa B*

Hae-Wan Leeabc, Dae-Ho Ahnabd, Suzanne C. Crawleyae, Jian-Dong Lif, James R. Gum Jr.ae, Carol B. Basbaumg, Nancy Q. Fanh, David E. Szymkowskih, Sang-Young Hanai, Bong H. Leeaj, Marvin H. Sleisengerae, and Young S. Kimaek

From the a Gastrointestinal Research Laboratory, Veterans Affairs Medical Center, San Francisco, California 94121, the Departments of e Medicine and g Anatomy, University of California, San Francisco, California 94143, the f Gonda Department of Cell and Molecular Biology, House Ear Institute, and the Department of Otolaryngology, University of Southern California, Los Angeles, California 90057, and h Roche Bioscience, Palo Alto, California 94304

MUC2 is a secretory mucin normally expressed by goblet cells of the intestinal epithelium. It is overexpressed in mucinous type colorectal cancers but down-regulated in colorectal adenocarcinoma. Phorbol 12-myristate 13-acetate (PMA) treatment of colon cancer cell lines increases MUC2 expression, so we have undertaken a detailed analysis of the effects of PMA on the promoter activity of the 5'-flanking region of the MUC2 gene using stably and transiently transfected promoter reporter vectors. Protein kinase C inhibitors (bisindolylmaleimide, calphostin C) and inhibitors of mitogen-activated protein/extracellular signal regulated kinase kinase (MEK) (PD98059 and U0126) suppressed up-regulation of MUC2. Src tyrosine kinase inhibitor PP2, a protein kinase A inhibitor (KT5720), and a p38 inhibitor (SB 203580) did not affect transcription. Western blotting and reverse transcription-PCR analysis confirmed these results. In addition, co-transfections with mutants of Ras, Raf, and MEK showed that the induction of MUC2 promoter activity by PMA required these three signaling proteins. Our results demonstrate that PMA activates protein kinase C, stimulating MAP kinase through a Ras- and Raf-dependent mechanism. An important role for nuclear factor kappa B (NF-kappa B) was also demonstrated using the inhibitor caffeic acid phenethyl ester and electrophoretic mobility shift assays. Such identification of pathways involved in MUC2 up-regulation by PMA in the HM3 colon cancer cell line may serve as a model for the effects of cytokines and growth factors, which regulate MUC2 expression during the progression of colorectal cancer.

* This work was supported by the Department of Veterans Affairs Medical Research Service, United States Public Health Service Grant CA 24321 from the National Institutes of Health and the Theodora Betz Foundation Fund.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

b Both authors contributed equally to this work.

c Present address: Dept. of Surgery, Chunchon Sacred Heart Hospital, Chunchon, Korea 200-060.

d Present address: Dept. of Surgery, College of Medicine, Pundang CHA Hospital, Kyonggi-do, 463-712, Korea.

i Present address: Dept. of Medicine, Dong-A University College of Medicine, Pusan, Korea 602-715.

j Present address: Dept. of General Surgery, Hallym University, Chunchon, Korea 431-070.

k To whom correspondence should be addressed: Gastrointestinal Research Laboratory (151M2), Veterans Affairs Medical Center, 4150 Clement St., San Francisco, CA 94121. Tel.: 415-750-2095; Fax: 415-750-6972; E-mail: youngk@itsa.ucsf.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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