Coregulatory protein-orphan nuclear receptor interactions in the human adrenal cortex.
The capacity of the adrenal to produce steroids is controlled in part through the transcriptional regulation of steroid enzymes. The orphan nuclear receptor steroidogenic factor 1 (SF-1) is central to the transcriptional regulation of all steroid hydroxylase enzymes, whereas nur77 can preferentially regulate steroid enzyme genes relevant to cortisol production. We hypothesised that, in the presence of secretagogues, SF-1 and nur77 may differentially interact with coregulatory proteins in the human adrenal cortex. Both coregulatory proteins, steroid receptor coactivator (SRC-1) and silencing mediator for retinoid and thyroid hormones (SMRT), were found to be expressed in the zona fasciculata and reticularis in the human adrenal cortex, but were largely absent from the zona glomerulosa. Both coregulatory proteins were colocalised with SF-1 and nur77. In the H295R adrenal tumour cell line, SF-1 and nur77 transcripts were increased in cells in the presence of forskolin, whereas nur77 mRNA was also induced with angiotensin II (AII). The coactivator SRC-1 mRNA was increased in the presence of both forskolin and AII. Forskolin induced recruitment of SRC-1 to the SF-1 response element and induced SRC-1-SF-1 interactions, whereas AII increased recruitment of SRC-1 to the nur77 response element and induced SRC-1-nur77 interactions. The corepressor SMRT interacted with SF-1 in the presence of AII and with nur77 in cells treated with forskolin. Orphan nuclear receptor-coregulatory protein interactions may have consequences for the regulation of key steroidogenic enzymes in the human adrenal cortex.
Department of Surgery, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Sinead N
SN
Kelly
T Joseph
TJ
McKenna
Leonie S
LS
Young
D000302:Adrenal Cortex / Q000737:chemistry*; D000804:Angiotensin II / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000032:analysis* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D051548:Histone Acetyltransferases; D018398:Homeodomain Proteins; D006801:Humans; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D025941:Protein Interaction Mapping / Q000379:methods; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis* / Q000235:genetics; D011987:Receptors, Steroid / Q000032:analysis* / Q000235:genetics; D012097:Repressor Proteins / Q000032:analysis*; D054339:Steroidogenic Factor 1; D013268:Stimulation, Chemical; D014157:Transcription Factors / Q000032:analysis* / Q000235:genetics; D015383:Zona Fasciculata / Q000737:chemistry; D015385:Zona Reticularis / Q000737:chemistry
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C539130:NCOR2 protein, human; C539821:NR4A1 protein, human; C515057:NR5A1 protein, human; D056985:Nuclear Receptor Co-Repressor 2; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; D000804:Angiotensin II; D005576:Colforsin; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1