COUP-TF and transcriptional co-regulators in adrenal steroidogenesis.
Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) and steroidogenic factor-1 (SF-1) play key roles in the transcriptional regulation of steroidogenic P450 genes. Transfection studies showed that SF-1 activated bovine CYP17 promoter activity, whereas COUP-TFs repressed it from the CRS2 element in a mutually exclusive manner in mouse adrenocortical Y-1 cells. COUP-TFI and SF-1 competitively bind to the Ad5 element of the human CYP11B2 gene promoter. Unexpectedly, overexpression of COUP-TFI increased the CYP11B2 promoter activity, whereas overexpression of SF-1 repressed it in human adrenocortical H295R cells. In cortisol-producing adrenal cortical adenomas, down-regulation of nuclear receptors, including COUP-TFs was found. We therefore screened for COUP-TFI-interacting proteins using a yeast two-hybrid system and have identified Ubc9 and PIAS1, SUMO-1 conjugating enzyme and ligase, respectively. Coexpression of Ubc9 and PIAS1 synergistically enhanced COUP-TFI-mediated trans-repression of CYP17 gene as well as transactivation of CYP11B2 gene. The SUMOylation-defective mutants of these proteins continued to function as co-regulators of COUP-TFI. These findings indicate that Ubc9 and PIAS1 can function as transcriptional co-regulators of COUP-TFI to modulate adrenal cortical steroidogenesis in a SUMOylation-independent manner.
Shibata
Hirotaka
H
Health Center, Keio University, Tokyo, Japan. hiro-405@cb3.so-net.ne.jp
Kobayashi
Sakiko
S
Kurihara
Isao
I
Suda
Noriko
N
Yokota
Kenichi
K
Murai
Ayano
A
Ikeda
Yayoi
Y
Saito
Ikuo
I
Rainey
William E
WE
Saruta
Takao
T
D000302:Adrenal Cortex / Q000378:metabolism*; D000818:Animals; D051836:COUP Transcription Factors; D002417:Cattle; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D018398:Homeodomain Proteins; D006801:Humans; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid / Q000378:metabolism* / Q000502:physiology; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics; D054339:Steroidogenic Factor 1; D013256:Steroids / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D044763:Ubiquitin-Conjugating Enzymes / Q000502:physiology; D000098843:Ubiquitin-Conjugating Enzyme UBC9
D051836:COUP Transcription Factors; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C515057:NR5A1 protein, human; D050828:Protein Inhibitors of Activated STAT; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D054339:Steroidogenic Factor 1; D013256:Steroids; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9