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Originally published In Press as doi:10.1074/jbc.M102063200 on June 15, 2001

J. Biol. Chem., Vol. 276, Issue 37, 34888-34895, September 14, 2001
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ERKs Regulate Cyclic AMP-induced Steroid Synthesis through Transcription of the Steroidogenic Acute Regulatory (StAR) Gene*

Shân L. GylesDagger §, Chris J. BurnsDagger §, Barbara J. WhitehouseDagger , David SugdenDagger , Phil J. Marsh||, Shanta J. PersaudDagger , and Peter M. JonesDagger **

From the Dagger  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

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.


* This work was supported by Wellcome Trust Grant 054789/Z/98/Z and a research and development grant from the Guy's and St. Thomas's Charitable Foundation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors share first authorship of this study.

A Biotechnology and Biological Sciences Research Council postgraduate student.

** To whom correspondence should be addressed: Endocrinology and Reproduction Research Group, New Hunt's House, 3rd Fl. North, GKT School of Biomedical Sciences, King's College London, London SE1 1UL, UK. Tel.: 44-207-848-6273; Fax: 44-207-848-6280; E-mail: peter.jones@kcl.ac.uk.


Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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