ERKs Regulate Cyclic AMP-induced Steroid Synthesis through Transcription of the Steroidogenic Acute Regulatory (StAR) Gene

Abstract

Cyclic AMP-dependent expression of the steroidogenic acute regulatory (StAR) protein is thought to be the controlling step for steroid production, but the mechanisms through which external signals are translated into increased transcription of the StAR gene are unknown. We demonstrate that cyclic AMP-induced steroid synthesis is dependent upon the phosphorylation and activation of ERKs and that ERK activation results in enhanced phosphorylation of SF-1 and increased steroid production through increased transcription of the StAR gene. Adenylate cyclase activation with forskolin (FSK) caused a time-dependent increase in ERK activity and translocation from cytoplasm to nucleus, which correlated with an increase in StAR mRNA levels, StAR protein accumulation, and steroidogenesis. Similarly, ERK inhibition led to a reduction in the levels of FSKstimulated StAR mRNA, StAR protein, and steroid secretion. These effects were attributed to the finding that ERK activity is required for SF-1 phosphorylation, a transcription factor required for the regulation of StAR gene transcription. This conclusion was supported by our demonstration of an ERK-dependent increase in the binding of SF-1 from FSK-treated Y1 nuclei to three consensus double-stranded DNA sequences from the StAR promoter region. These observations suggest that the activation of ERK2/1 by increasing cAMP is an obligatory and regulated stage in the stimulation of steroid synthesis by cyclic AMP-generating stimuli.

Repression of DAX-1 and Induction of SF-1 Expression

“…In contrast, the role of ERK2/1 in the activation of adrenal steroidogenesis by ACTH or forskolin is controversial. Thus, forskolin was found to increase StAR expression and steroidogenesis in Y1 mouse adrenocortical tumor cells and to activate ERK2/1 (21). In contrast, in bovine fasciculata and rat glomerulosa cells, ACTH treatment did not lead to p42/44 mitogen-activated protein kinase (ERK2/1) activation (40,41).…”

“…Furthermore, SF-1 has also been shown to regulate the expression of genes encoding cytochrome P450 hydroxylases and to efficiently transactivate the StAR gene in transient transfection assays in various cell types (13,15,16,19). Although the extent of SF-1 involvement in the regulation of StAR gene expression may present species-and cell type-dependent differences (20), it appears that activation of the cAMP-signaling pathway leads to increased phosphorylation (21) and/or expression (22) of SF-1 protein.…”

Janus Kinase 2 and Calcium Are Required for Angiotensin II-dependent Activation of Steroidogenic Acute Regulatory Protein Transcription in H295R Human Adrenocortical Cells

“…As stated previously, both positive and negative effects of ERK1/2 activation have been reported for cAMP-stimulated StAR expression and steroid production. In Y1 mouse adrenal cells PD098059 treatment decreased the forskolin-stimulated increase in StAR steady-state mRNA levels by ϳ50% (44). In primary cultures of rat granulosa the MEK-1 inhibitor U1026 inhibited follicle-stimulating hormonestimulated increase in StAR mRNA (48), while in a transformed cell line U1026 potentiated the stimulatory effects of follicle-stimulating hormone on StAR protein levels (47).…”

Downregulation of progesterone biosynthesis in rat granulosa cells by adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) bran extracts

“…45 Of the mitogen-activated protein kinase (MAPK) signaling molecules, ERK1/2 have been implicated in the modulation of steroidogenesis in granulosa cells [45][46][47] and other steroidogenic cells. 48 Our results indicated that ABM-Bu-G inhibited ERK1/2 phosphorylation in rat granulosa cells. These results imply that ERK1/2 signalling might be involved in the inhibition of progesterone secretion caused by adlay bran extracts in rat granulosa cells.…”