Induction of Mad expression leads to augmentation of insulin gene transcription

Giovanni Patané, Hideaki Kaneto, Elena Toschi, Arun Sharma, Sanjeev Gupta, Gordon C. Weir

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Insulin gene transcription is critical for the maintenance of pancreatic β-cell differentiation and insulin production. In this study, we found that the basic helix-loop-helix transcription factor Mad, which usually acts as a repressor to c-Myc, enhances insulin gene transcription. In isolated rat islets adenoviral overexpression of Mad augmented insulin mRNA expression and insulin protein content, as well as glucokinase and GLUT2 mRNA expression. Also, Mad overexpression upregulated insulin promoter activity in β-cell-derived cell lines, MIN6 and βTC1, as well as in non-insulin producing liver cell line, HepG2. Mad overexpression in rat islets enhanced PDX-1 expression and its DNA binding activity. We found that Mad mediated increased PDX-1 expression by an E-box dependent transcriptional regulation of the PDX-1 gene. That the effects of Mad on insulin expression were mediated through PDX-1 was further substantiated by studies showing inhibition of insulin promoter activation by Mad in the presence of mutated PDX-1 binding site. Although Mad functions as a negative regulatory factor for multiple target genes, these studies establish the fact that Mad can also function as a positive regulatory factor for insulin gene transcription. Such regulation of insulin expression by Mad with modulation of PDX-1 expression and DNA binding activity could offer useful therapeutic and/or experimental tools to promote insulin production in appropriate cell types.

Original languageEnglish (US)
Pages (from-to)1199-1208
Number of pages10
JournalBiochemical and Biophysical Research Communications
Volume303
Issue number4
DOIs
StatePublished - Apr 18 2003
Externally publishedYes

Keywords

  • Glucokinase
  • Glut-2
  • Insulin content
  • Insulin gene expression
  • Mad
  • PDX-1
  • Rat pancreatic islets
  • c-Myc
  • β-Cell

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

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