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J. Biol. Chem., Vol. 282, Issue 13, 9883-9894, March 30, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/13/9883    most recent M606754200v1 Alert me when this article is cited 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Su, H.-W. Articles by Tang, M.-J. Search for Related Content PubMed PubMed Citation Articles by Su, H.-W. Articles by Tang, M.-J. Social Bookmarking                      What's this?

Cell Confluence-induced Activation of Signal Transducer and Activator of Transcription-3 (Stat3) Triggers Epithelial Dome Formation via Augmentation of Sodium Hydrogen Exchanger-3 (NHE3) Expression^*

Hsiao-Wen Su, Hsuan-Heng Yeh, Shainn-Wei Wang, Meng-Ru Shen^¶, Tsu-Ling Chen^||, Pawel R. Kiela^**, Fayez K. Ghishan^**, and Ming-Jer Tang^||1

From the Institute of Basic Medical Sciences, Institute of Molecular Medicine, ^¶Department of Pharmacology, ^||Department of Physiology, and Center for Gene Regulation and Signal Transduction Research, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan and the ^**Departments of Pediatrics and Physiology, Steele Children's Research Center, University of Arizona Health Sciences Center, Tucson, Arizona 85724

Cell confluence induces the activation of signal transducer and activator of transcription-3 (Stat3) in various cancer and epithelial cells, yet the biological implications and the associated regulatory mechanisms remain unclear. Because confluent polarized epithelia demonstrate dome formation and sodium influx that mimic the onset of differentiation, we sought to elucidate the role of Stat3 in association with the regulation of selective epithelial transporters in this biological phenomenon. This study established the correlation between Stat3 activation and cell confluence-induced dome formation in Madin-Darby canine kidney cells (MDCK) by following Stat3 activation events in dome-forming cells. Epifluorescent and confocal microscopy provided evidence showing specific localization of phosphorylated Stat3 Tyr⁷⁰⁵ in the nuclei of dome-forming cells at initial stages. The relationship was further elucidated by the establishment of tetracycline-inducible expression of constitutive Stat3 mutant (Stat3-C) in MDCK cells or expression of dominant negative Stat3 (Stat3-D) stable cell lines (MDCK and NMuMG). Dome formation was promoted by the expression of Stat3-C but inhibited by Stat3-D. Two trans-epithelial transporters, NHE3 and ENaC -subunit, were found to be increased during cell confluence. Interestingly, NHE3 expression could be specifically up-regulated by Stat3-C but inhibited by Stat3-D through promoter regulation, whereas NHE1 and ENaC -subunit were not affected by Stat3 expression. Application of NHE3 shRNA, NHE3 inhibitors (EIPA and S3226) suppressed confluence-induced dome formation in MDCK or NMuMG cells. These results demonstrate a cell confluence-induced Stat3 signaling pathway in epithelial cells in triggering dome formation through NHE3 augmentation.

Received for publication, July 17, 2006 , and in revised form, January 10, 2007.

^* This work was supported by National Science Council Grant NSC 94-2320-B006-060 and the Ministry of Education Program for Promoting Academic Excellence in Universities Grant 91-B-FA09-1-4 (to M. J. T.) and by National Institutes of Health Grant 5R01-DK41274 (to F. K. G.). 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: Dept. of Physiology, College of Medicine, National Cheng Kung University, 1 Da-Hsueh Road, Tainan 701, Taiwan. Tel.: 886-6-235-3535, ext. 5425; Fax: 886-6-236-2780; E-mail: mjtang1{at}mail.ncku.edu.tw.

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				H.-W. Su, S.-W. Wang, F. K. Ghishan, P. R. Kiela, and M.-J. Tang Cell confluency-induced Stat3 activation regulates NHE3 expression by recruiting Sp1 and Sp3 to the proximal NHE3 promoter region during epithelial dome formation Am J Physiol Cell Physiol, January 1, 2009; 296(1): C13 - C24. [Abstract] [Full Text] [PDF]