Identification of retinoic acid-responsive elements on the HNF1alpha and HNF4alpha genes.
Hepatocyte nuclear factor 1alpha (HNF1alpha) and HNF4alpha are liver-selective transcription factors and are essential for hepatocyte differentiation. This study demonstrates that HNF1alpha as well as HNF4alpha genes contain a direct repeat with a space of one nucleotide (DR1)-retinoic acid (RA) response element that can be bound and regulated by RA and retinoid x receptor alpha (RXRalpha) complex. Transient transfection experiments showed that RA increased the promoter activity of the HNF1alpha and HNF4alpha genes in Hep3B cells. Overexpression of RXRalpha further enhanced the activities of both genes. Two putative RXRalpha binding sites on the HNF1alpha (-295 to -276) and HNF4alpha (-418 to -399) genes have been characterized. By transient transfection, both sites positively responded to RA, and overexpression of RXRalpha in Hep3B cells increased the regulatory effect. Gel mobility shift assay demonstrated that these two DR-1 sites could be bound by RXRalpha specifically. These data suggest that the differentiation effect of RA on hepatocyte may be due to direct interaction of RXRalpha with the RA-responsive elements on the HNF1alpha and HNF4alpha genes.
Qian
A
A
Department of Pathology, Harbor-UCLA Medical Center, Torrance, California, 90509, USA.
Cai
Y
Y
Magee
T R
TR
Wan
Y J
YJ
D000077556:Alitretinoin; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D001665:Binding Sites; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C403128:MLX protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D000077556:Alitretinoin; D014212:Tretinoin; D004247:DNA