Hepatocyte nuclear factor-3 homologue 1 (HFH-1) represses transcription of smooth muscle-specific genes.
Results show that smooth muscle-specific promoters represent novel downstream targets of the winged helix factor hepatocyte nuclear factor-3 homologue 1 (HFH-1). HFH-1 strongly represses telokin promoter activity when overexpressed in A10 vascular smooth muscle cells. HFH-1 was also found to repress transcription of several other smooth muscle-specific promoters, including the SM22alpha promoter. HFH-1 inhibits telokin promoter activity, by binding to a forkhead consensus site located within an AT-rich region of the telokin promoter. The DNA-binding domain alone was sufficient to mediate inhibition, suggesting that binding of HFH-1 blocks the binding of other positive-acting factors. HFH-1 does not disrupt serum response factor binding to an adjacent CArG box within the telokin promoter, implying that HFH-1 must compete with other unidentified trans-activators to mediate repression. The localization of HFH-1 mRNA to the epithelial cell layer of mouse bladder and stomach implicates HFH-1 in repressing telokin expression in epithelial cells. This suggests that cell-specific expression of telokin is likely mediated by both positive-acting factors in smooth muscle cells and negative-acting factors in nonmuscle cell types. We propose a model in which the smooth muscle specificity of the telokin promoter is regulated by interactions between positive- and negative-acting members of the hepatocyte nuclear factor-3/forkhead family of transcription factors.
Hoggatt
A M
AM
Department of Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, USA.
Kriegel
A M
AM
Smith
A F
AF
Herring
B P
BP
D000818:Animals; D015152:Blotting, Northern; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism; D051858:Forkhead Transcription Factors; D005753:Gastric Mucosa / Q000378:metabolism; D015723:Gene Library; D017403:In Situ Hybridization; D051379:Mice; D008840:Microfilament Proteins; D008954:Models, Biological; D008957:Models, Genetic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009219:Myosin-Light-Chain Kinase; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments; D010455:Peptides; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D012260:Ribonucleases / Q000378:metabolism; D026362:Serum Response Factor; D014018:Tissue Distribution; D015534:Trans-Activators / Q000235:genetics* / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D001743:Urinary Bladder / Q000378:metabolism
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C107579:Foxq1 protein, mouse; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D012333:RNA, Messenger; D026362:Serum Response Factor; C058992:Tagln protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C051615:transgelin; C060640:telokin; D004247:DNA; D009219:Myosin-Light-Chain Kinase; D012260:Ribonucleases