HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 283, Issue 40, 26869-26878, October 3, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/40/26869    most recent M802507200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Song, K. S. Articles by Yoon, J.-H. Search for Related Content PubMed PubMed Citation Articles by Song, K. S. Articles by Yoon, J.-H. Social Bookmarking                      What's this?

cAMP-responding Element-binding Protein and c-Ets1 Interact in the Regulation of ATP-dependent MUC5AC Gene Expression^*

Kyoung Seob Song, Tae-Jin Lee, Kyubo Kim^¶, Kwang Chul Chung^||, and Joo-Heon Yoon^¶**1

From the Airway Mucus Institute, ^¶Department of Otorhinolaryngology, ^**Brain Korea 21 for Medical Sciences, Research Center for Human Natural Defense System, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-gu, Seoul 120-752, the Department of Anatomy, College of Medicine, Yeungnam University, 317-1 Daemyoung-Dong Namgu-Gu, Taegu 705-717, and the ^||Department of Biology, College of Sciences, Yonsei University, 134 Shinchon-Dong, Seodaemun-gu, Seoul 120-749, Korea

Exogenous ATP activates purinoreceptors on the cell surface that regulate diverse cellular functions, including mucous cell secretion in the respiratory epithelium. In this study, ATP increased MUC5AC mRNA in primary human nasal epithelial cells and in NCI-H292 pulmonary adenocarcinoma cells in vitro. ATP-induced MUC5AC mRNA was mediated by phospholipase Cβ3. A dominant-negative mutation in the PDZ binding domain of PLCβ3 inhibited ATP-induced MUC5AC gene expression. ATP sequentially activated the phosphorylation of Akt, ERK1/2, p38, RSK1, and cAMP-responding element-binding protein (CREB) in a protein kinase C-independent manner. ATP-induced MUC5AC mRNA levels were regulated by CREB via direct interaction with c-Ets1 on the MUC5AC gene promoter (located –938 to –930). Effects of CREB and c-Ets1 were additive. Inhibition of either CREB or c-Ets1 inhibited ATP-induced MUC5AC gene expression. Stimulation with ATP caused the direct binding of CREB and c-Ets1 to the MUC5AC promoter, increasing the phosphorylation of c-Ets1. Chromatin immunoprecipitation assays demonstrated that in the presence of ATP, both c-Ets1 and CREB bound to the MUC5AC promoter. The effects of exogenous ATP on MUC5AC gene expression are mediated by a complex regulatory cascade controlling interactions between CREB and c-Ets1 that bind to a promoter element in the MUC5AC gene enhancing MUC5AC gene transcription. ATP-dependent activation of MUC5AC gene expression via CREB-c-Ets1 may contribute to mucous cell hypersecretion associated with common respiratory disorders.

Received for publication, April 1, 2008 , and in revised form, July 22, 2008.

^* This work was supported by Korea Science and Engineering Foundation Grant R11-2007-040-02001-0 funded by the Korean Government (MOST) (to J. H. Y.) and Korea Research Foundation Grant KRF-2005-050-C00005 (to K. S. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 134 Shinchon-Dong, Seodaemun-gu, Seoul 120-752, Korea. Tel.: 82-2-2228-3610; Fax: 82-2-393-0580; E-mail: jhyoon{at}yuhs.ac.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?