Expression profiles of COUP-TF, DAX-1, and SF-1 in the human adrenal gland and adrenocortical tumors: possible implications in steroidogenesis.
Chicken ovalbumin upstream promoter-transcription factor (COUP-TF), DAX-1, and steroidogenic factor-1 (SF-1) are orphan members of the nuclear hormone receptor superfamily. COUP-TF and DAX-1 have been shown to negatively regulate the transcriptional activity of SF-1, a steroidogenic cell-specific activator of various steroidogenic cytochrome P450 genes. We therefore examined the expression levels and immunolocalization of COUP-TF, DAX-1, and SF-1 in human adrenal gland (NL) and adrenocortical adenomas, and compared the results with CYP17 expression levels and its enzyme activities to study their potential correlation with adrenocortical steroidogenesis. In NL (n = 10), expressions of COUP-TF, DAX-1, and SF-1 were detected in the nuclei of adrenocortical cells, but not in the medulla. In cortisol-producing adenomas causing Cushing syndrome (CS, n = 20), CYP17 expression was upregulated (298 +/- 2% vs NL 98 +/- 4%), whereas expression levels of both COUP-TFs (COUP-TFI, 52 +/- 5% vs NL 98 +/- 4%; COUP-TFII, 18 +/- 4% vs NL 98 +/- 4%) and DAX-1 (42 +/- 4% vs NL 100 +/- 4%) were reduced. In deoxycorticosterone-producing adenomas (DOC, n = 2), on the other hand, CYP17 expression was extremely reduced (8 and 12% vs NL 98 +/- 4%), whereas DAX-1 expression increased markedly (350 and 360% vs NL 100 +/- 4%). Expression levels of SF-1 did not differ between NL (100 +/- 8%) and CS (106 +/- 10%), but its expression appeared to be decreased in DOC (25 and 20%). These results showed CYP17 expression to be upregulated and downregulated in CS and DOC, respectively, in a manner reciprocal to that of its repressors, COUP-TF and/or DAX-1. In summary, the results indicate that co-localization of COUP-TF, DAX-1, and SF-1 in NL was lost in adrenocortical tumors and that these orphan receptors play an important role in the regulation of steroidogenesis in human adrenals.
Shibata
H
H
Health Center, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, 160-8582, Japan. hiro-405@cb3.so-nat.ne.jp
Ikeda
Y
Y
Mukai
T
T
Morohashi
K
K
Kurihara
I
I
Ando
T
T
Suzuki
T
T
Kobayashi
S
S
Murai
M
M
Saito
I
I
Saruta
T
T
D000236:Adenoma / Q000378:metabolism*; D000306:Adrenal Cortex Neoplasms / Q000378:metabolism*; D000311:Adrenal Glands / Q000378:metabolism*; D000328:Adult; D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003900:Desoxycorticosterone / Q000096:biosynthesis; D005260:Female; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis*; D011987:Receptors, Steroid; D012097:Repressor Proteins; D013254:Steroid 17-alpha-Hydroxylase / Q000096:biosynthesis; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000096:biosynthesis*
D051837:COUP Transcription Factor II; D051836:COUP Transcription Factors; D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D003900:Desoxycorticosterone; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D012097:Repressor Proteins; D013254:Steroid 17-alpha-Hydroxylase; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; C095569:NR2F2 protein, human