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J. Biol. Chem., Vol. 281, Issue 50, 38385-38395, December 15, 2006

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The PDX1 Homeodomain Transcription Factor Negatively Regulates the Pancreatic Ductal Cell-specific Keratin 19 Promoter^*

Therese B. Deramaudt, Mira M. Sachdeva, Melanie P. Wescott, Yuting Chen, Doris A. Stoffers, and Anil K. Rustgi¹

From the Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center and Division of Endocrinology, Diabetes and Metabolism, the Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Keratin 19 is a member of the cytokeratin family that is critical for maintenance of cellular architecture and organization, especially of epithelia. The pancreas has three distinct cell types, ductal, acinar, and islet, each with different functions. Embryologically, the pancreatic and duodenal homeobox 1 (PDX1) homeodomain protein is critical for the initiation of all pancreatic lineages; however, the later differentiation of the endocrine pancreas is uniquely dependent upon high PDX1 expression, whereas PDX1 is down-regulated in the ductal and acinar cell lineages. We find that this down-regulation may be required for normal ductal expression of cytokeratin K19. The K19 promoter-reporter gene assay demonstrates that ectopic PDX1 inhibits K19 reporter gene activity in primary pancreatic ductal cells. This is reinforced by our findings that retrovirally mediated stable transduction of PDX1 in primary pancreatic ductal cells suppresses K19 expression, and short interfering RNA to PDX1 in Min6 insulinoma cells results in the induction of normally undetectable K19. Complementary functional and biochemical approaches led to the unexpected finding that a multimeric complex of PDX1 and two members of the TALE homeodomain factor family, MEIS1a and PBX1b, regulates K19 gene transcription through a specific cis-regulatory element (–341 to –325) upstream of the K19 transcription start site. These data suggest a unifying mechanism whereby PDX1, myeloid ecotropic viral insertion site (MEIS), and pre-B-cell leukemia transcription factor 1 (PBX) may regulate ductal and acinar lineage specification during pancreatic development. Specifically, concomitant PDX1 suppression and MEIS isoform expression result in proper ductal and acinar lineage specification. Furthermore, PDX1 may inhibit the ductal differentiation program in the pancreatic endocrine compartment, particularly beta cells.

Received for publication, June 20, 2006 , and in revised form, October 12, 2006.

^* This work was supported by NIDDK, National Institutes of Health Grants R01 DK50306 (to A. K. R., T. B. D., Y. C., and D. A. S.), R01 DK068157 (to D. A. S.), and P01 DK49210 (to D. A. S. and M. M. S.), and by the National Pancreas Foundation (to T. B. D.), Department of Genetics Training Grant 5-T32-GM-08216-19 (to M. M. S.), NIDDK, National Institutes of Health Center for Molecular Studies in Digestive and Liver Diseases Grant P30 DK50306 and its Morphology, Molecular Biology, Mouse, and Cell Culture Core Facilities, and the Penn Diabetes and Endocrinology Research Center (Grant P30 DK19525) of the Institute of Diabetes, Obesity, and Metabolism. 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: GI division, 600 CRB, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104. Tel.: 215-898-0154; Fax: 215-573-5412; E-mail:: anil2{at}mail.med.upenn.edu.

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