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

J. Biol. Chem., Vol. 280, Issue 46, 38438-38444, November 18, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/46/38438    most recent M508594200v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Van Velkinburgh, J. C. Articles by Stein, R. Search for Related Content PubMed PubMed Citation Articles by Van Velkinburgh, J. C. Articles by Stein, R. Social Bookmarking                      What's this?

Interactions between Areas I and II Direct pdx-1 Expression Specifically to Islet Cell Types of the Mature and Developing Pancreas^*

From the Department of Molecular Physiology and Biophysics, Vanderbilt Medical Center, Nashville, Tennessee 37232

PDX-1 regulates transcription of genes involved in islet cell function and pancreas development. Islet-specific expression is controlled by 5'-flanking sequences from base pair (bp) -2917 to -1918 in transgenic experiments, which encompasses both conserved (i.e. Area I (bp -2761/-2457), Area II (bp -2153/-1923)) and non-conserved pdx-1 sequences. However, only an Area II-driven transgene is independently active in vivo, albeit in only a fraction of islet PDX-1-producing cells. Our objective was to identify the sequences within the -2917/-1918-bp region that act in conjunction with Area II to allow comprehensive expression in islet PDX-1⁺ cells. In cell line-based transfection assays, only Area I effectively potentiated Area II activity. Both Area I and Area II functioned in an orientation-independent manner, whereas synergistic, enhancer-like activation was uniquely found with duplicated Area II. Chimeras of Area II and the generally active SV40 enhancer or the cell-specific insulin enhancer suggested that islet cell-enriched activators were necessary for Area I activation, because Area II-mediated stimulation was reduced by the SV40 enhancer and activated by the insulin enhancer. Several conserved sites within Area I were important in Area I/Area II activation, with binding at bp -2614/-2609 specifically controlled by Nkx2.2, an insulin gene regulator that is required for terminal cell differentiation. The ability of Area I to modulate Area II activation was also observed in vivo, as an Area I/Area II-driven transgene recapitulated the endogenous pdx-1 expression pattern in developing and adult islet cells. These results suggest that Area II is a central pdx-1 control region, whose islet cell activity is uniquely modified by Area I regulatory factors.

Received for publication, August 4, 2005

^* This work was supported by National Institutes of Health Grants RO1 DK-50203 (to R. S.), Training Grant 5T32 CA09385-18 (to J. C. V. V.), and Juvenile Diabetes Research Foundation Postdoctoral 3-2003-579 (to I. A.). The transgenic mice were developed with the assistance of Transgenic/ES Cell Shared Resource Grants CA68485 and DK20593 and by the Molecular Biology Core Laboratory by the Vanderbilt University Diabetes Research and Training Center Public Health Service Grant P60 DK20593. 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 Current address: National Center for Toxicogenomics, National Institutes of Health, NIEHS, Research Triangle Park, NC 27709.

² To whom correspondence should be addressed. Tel.: 615-322-7026; Fax: 615-322-7236; E-mail: Roland.Stein{at}vanderbilt.edu.

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

This article has been cited by other articles:

				A. M. Vanhoose, S. Samaras, I. Artner, E. Henderson, Y. Hang, and R. Stein MafA and MafB Regulate Pdx1 Transcription through the Area II Control Region in Pancreatic {beta} Cells J. Biol. Chem., August 15, 2008; 283(33): 22612 - 22619. [Abstract] [Full Text] [PDF]

				P. O. Wiebe, J. D. Kormish, V. T. Roper, Y. Fujitani, N. I. Alston, K. S. Zaret, C. V. E. Wright, R. W. Stein, and M. Gannon Ptf1a Binds to and Activates Area III, a Highly Conserved Region of the Pdx1 Promoter That Mediates Early Pancreas-Wide Pdx1 Expression Mol. Cell. Biol., June 1, 2007; 27(11): 4093 - 4104. [Abstract] [Full Text] [PDF]

				K. Eto, V. Kaur, and M. K. Thomas Regulation of Pancreas Duodenum Homeobox-1 Expression by Early Growth Response-1 J. Biol. Chem., March 2, 2007; 282(9): 5973 - 5983. [Abstract] [Full Text] [PDF]

				M. J. Doyle, Z. L. Loomis, and L. Sussel Nkx2.2-repressor activity is sufficient to specify {alpha}-cells and a small number of {beta}-cells in the pancreatic islet Development, February 1, 2007; 134(3): 515 - 523. [Abstract] [Full Text] [PDF]

				J. C. Raum, K. Gerrish, I. Artner, E. Henderson, M. Guo, L. Sussel, J. C. Schisler, C. B. Newgard, and R. Stein FoxA2, Nkx2.2, and PDX-1 Regulate Islet {beta}-Cell-Specific mafA Expression through Conserved Sequences Located between Base Pairs -8118 and -7750 Upstream from the Transcription Start Site Mol. Cell. Biol., August 1, 2006; 26(15): 5735 - 5743. [Abstract] [Full Text] [PDF]

				Y. Fujitani, S. Fujitani, D. F. Boyer, M. Gannon, Y. Kawaguchi, M. Ray, M. Shiota, R. W. Stein, M. A. Magnuson, and C. V.E. Wright Targeted deletion of a cis-regulatory region reveals differential gene dosage requirements for Pdx1 in foregut organ differentiation and pancreas formation Genes & Dev., January 15, 2006; 20(2): 253 - 266. [Abstract] [Full Text] [PDF]