The AP-1 family member FOS blocks transcriptional activity of the nuclear receptor steroidogenic factor 1.
Steroid production in the adrenal zona glomerulosa is under the control of angiotensin II (Ang II), which, upon binding to its receptor, activates protein kinase C (PKC) within these cells. PKC is a potent inhibitor of the steroidogenic enzyme CYP17. We have demonstrated that, in the ovary, PKC activates expression of FOS, a member of the AP-1 family, and increased expression of this gene is linked to CYP17 downregulation. However, the pathway and the molecular mechanism responsible for the inhibitory effect of PKC on CYP17 expression are not defined. Herein, we demonstrated that Ang II inhibited CYP17 through PKC and ERK1/2-activated FOS and that blocking FOS expression decreased PKC-mediated inhibition. Although CYP17 transcription was activated by the nuclear receptor SF-1, expression of FOS resulted in a decrease in SF-1-mediated gene transcription. FOS physically interacted with the hinge region of SF-1 and modulated its transactivity, thus preventing binding of cofactors such as SRC1 and CBP, which were necessary to fully activate CYP17 transcription. Collectively, these results indicate a new regulatory mechanism for SF-1 transcriptional activity that might influence adrenal zone-specific expression of CYP17, a mechanism that can potentially be applied to other steroidogenic tissues.
Sirianni
Rosa
R
Department of Pharmaco-Biology and Cell Biology, University of Calabria, Arcavacata di Rende (CS) 87036, Italy.
Nogueira
Edson
E
Bassett
Mary H
MH
Carr
Bruce R
BR
Suzuki
Takashi
T
Pezzi
Vincenzo
V
Andò
Sebastiano
S
Rainey
William E
WE
D000311:Adrenal Glands / Q000201:enzymology / Q000378:metabolism; D020013:Calcium Signaling; D018929:Cell Culture Techniques; D006801:Humans; D007150:Immunohistochemistry; D046228:Microarray Analysis; D051839:NFI Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D054339:Steroidogenic Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
D051839:NFI Transcription Factors; D054339:Steroidogenic Factor 1; D018808:Transcription Factor AP-1; D013254:Steroid 17-alpha-Hydroxylase; D011493:Protein Kinase C