The AP-1 family member FOS blocks transcriptional activity of the nuclear receptor steroidogenic factor 1

Abstract

SummarySteroid 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.

A Cell-Autonomous Molecular Cascade Initiated by AMP-Activated Protein Kinase Represses Steroidogenesis

“…c-Fos is known to inhibit steroidogenesis by repressing Star expression (36) and NR5A1 (SF1) transactivation properties (63). c-Fos was also found to be underexpressed in patients with polycystic ovarian syndrome (PCOS), a condition where patients produce excess androgens (64).…”

Acute and chronic regulation of aldosterone production

“…DAG-activated PKC, on the other hand, does not appear to increase CYP11B2 transcript levels, but does play a role in producing an aldosterone-secreting glomerulosa cell phenotype by inhibiting the expression of CYP17 (Bird et al, 1996; McEwan et al, 1999). This effect has been recently attributed to Fos-mediated repression of the CYP17 transcriptional activator, steroidogenic factor 1 (SF1) (Sirianni et al, 2010). On the other hand, there is evidence suggesting that certain PKC isoforms, such as PKC-epsilon may actually inhibit CYP11B2 expression via activation of ERK-1/2 (LeHoux and Lefebvre, 2006; Lehoux and Lefebvre, 2007).…”

JunB defines functional and structural integrity of the epidermo-pilosebaceous unit in the skin

“…Our results identified a specific enrichment of the JunB/AP1 motif during epidermal differentiation, which directly suppresses Notch signaling via physical interaction with the Notch1 and Notch4 promoters. AP-1 has also been implicated in transcriptional repression of matrix metalloproteinase-9 through recruitment of histone deacetylase-1 in response to interferon β 36 and 17a-hydroxylase-17,20-lyase via blocking transcriptional activity of the nuclear receptor steroidogenic factor-1 37 . In addition, anti-proliferative actions of JunB/AP1 family have been reported to be due to direct activation and induced expression of the cell cycle check point marker, p16 38 .…”