Suppression of MafA-dependent transcription by transforming growth factor-beta signaling.

MafA is a basic leucine zipper (b-Zip) type transcription factor that binds to the insulin promoter and regulates insulin transcription synergistically with Pdx-1 and NeuroD. Transforming growth factor-beta (TGF-beta) signaling has been reported to regulate activity of b-Zip transcription factor such as ATF-2 and acts as an important regulator of insulin gene transcription and pancreatic beta cell maintenance. To investigate the relationship between MafA-dependent transcriptional activation and TGF-beta signaling, we examined the effects of TGF-beta signal on MafA-dependent transactivation of the rat insulin II gene promoter (RIPII-251) and a synthetic MafA-dependent promoter. MafA-dependent activation of the reporters was inhibited in the presence of Smad2/Smad4 or Smad3/Smad4 and a constitutively active TGF-beta type I receptor and this inhibition was dependent upon the presence of MafA. Co-immunoprecipitation analyses revealed that MafA physically interacts with Smad2 or Smad3. These results suggest that MafA-dependent transcriptional activation is negatively regulated by TGF-beta signaling.