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 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 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 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.
Gyles
S L
SL
Endocrinology and Reproduction Research Group and The Randall Centre, Guy's, King's and St. Thomas's School of Biomedical Sciences, King's College London, London SE1 1UL, United Kingdom.
Burns
C J
CJ
Whitehouse
B J
BJ
Sugden
D
D
Marsh
P J
PJ
Persaud
S J
SJ
Jones
P M
PM
D000818:Animals; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013256:Steroids / Q000096:biosynthesis*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000098682:Steroidogenic Acute Regulatory Protein
D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013256:Steroids; D014157:Transcription Factors; D000098682:Steroidogenic Acute Regulatory Protein; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases