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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
ERKs Regulate Cyclic AMP-induced Steroid Synthesis
through Transcription of the Steroidogenic Acute Regulatory
(StAR) Gene*
Shân L.
Gyles §¶,
Chris J.
Burns §,
Barbara
J.
Whitehouse ,
David
Sugden ,
Phil J.
Marsh ,
Shanta J.
Persaud , and
Peter M.
Jones **
From the 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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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.
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