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Pdx-1 Is Not Sufficient for Repression of Proglucagon Gene Transcription in Islet or Enteroendocrine Cells

Department of Medicine, Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada M5G 2C4

Address all correspondence and requests for reprints to: Dr. Daniel J. Drucker, Toronto General Hospital, Banting and Best Diabetes Centre, 200 Elizabeth Street MBRW4R-402, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca.

Pdx-1 plays a key role in the development of the pancreas and the control of islet gene transcription and has also been proposed as a dominant regulator of the - vs. ß-cell phenotype via extinction of proglucagon expression. To ascertain the relationship between Pdx-1 and proglucagon gene expression, we examined the effect of enhanced pdx-1 expression on proglucagon gene expression in murine islet TC-1 and GLUTag enteroendocrine cells. Although adenoviral transduction increased the levels of pdx-1 mRNA transcripts and nuclear Pdx-1 protein, overexpression of pdx-1 did not repress endogenous proglucagon gene expression in TC-1 or GLUTag cells or murine islets. Immunohistochemical analysis of cells transduced with Ad-pdx-1 demonstrated multiple individual islet or enteroendocrine cells exhibiting both nuclear Pdx-1 and cytoplasmic glucagon-like peptide-1 immunopositivity. The failure of pdx-1 to inhibit endogenous proglucagon gene expression was not attributable to defects in Pdx-1 nuclear translocation or DNA binding as demonstrated using Western blotting and EMSA analyses. Furthermore, Ad-pdx-1 transduction did not repress proglucagon promoter activity in TC-1 or GLUTag cells. Taken together, these findings demonstrate that pdx-1 alone is not sufficient for specification of the hormonal phenotype or extinction of proglucagon gene expression in islet or enteroendocrine cells.

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