Suppression of MafA-dependent transcription by transforming growth factor-b signaling

MafA is a basic leucine zipper (b-Zip) type transcription factor that binds to the insulin promoter and regulates insulin transcriptionsynergistically with Pdx-1 and NeuroD. Transforming growth factor-b (TGF-b) signaling has been reported to regulate activity of b-Ziptranscription factor such as ATF-2 and acts as an important regulator of insulin gene transcription and pancreatic b cell maintenance. Toinvestigate the relationship between MafA-dependent transcriptional activation and TGF-b signaling, we examined the effects of TGF-bsignal 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 activeTGF-b type I receptor and this inhibition was dependent upon the presence of MafA. Co-immunoprecipitation analyses revealed thatMafA physically interacts with Smad2 or Smad3. These results suggest that MafA-dependent transcriptional activation is negatively regulatedby TGF-b signaling