ERKs regulate cyclic AMP-induced steroid synthesis through transcription of the steroidogenic acute regulatory (StAR) gene

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 increase d transcription of the StAR gene are unknown. We demonstrate that cyclic AM P-induced steroid synthesis is dependent upon the phosphorylation and activ ation of ERKs and that ERK activation results in enhanced phosphorylation o f SF-1 and increased steroid production through increased transcription of the StAR gene. Adenylate cyclase activation with forskolin (FSK) caused a t ime-dependent increase in ERK activity and translocation from cytoplasm to nucleus, which correlated with an increase in StAR mRNA levels, StAR protei n accumulation, and steroidogenesis. Similarly, ERK inhibition led to a red uction in the levels of FSK-stimulated 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 t he 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 o f ERK2/1 by increasing cAMP is an obligatory and regulated stage in the sti mulation of steroid synthesis by cyclic AMP-generating stimuli.