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Submitted on May 25, 2006
Accepted on December 29, 2006
Department of Biological Chemistry, The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
* To whom correspondence should be addressed. E-mail: orly{at}vms.huji.ac.il.
The first and key enzyme controlling the synthesis of steroid hormones is cholesterol side chain cleavage cytochrome P450 (P450scc, CYP11A1). This study sought to elucidate overlooked modes of regulation of P450scc transcription in the rodent placenta and ovary. Transcription of P450scc requires two clusters of cis-regulatory elements: a proximal element (-40) known to bind either activating protein 2 (AP-2) in the placenta, or steroidogenic factor 1 (SF-1) in the ovary, and a distal region of the promoter (-475/-447) necessary for potentiation of the AP-2/SF-1 dependent activity up to 7-fold. In primary cultures of mouse trophoblast giant cells and rat ovarian granulosa cells, binding of trans-factors to the distal regulatory sequences generated transcriptional activity in a tissue specific pattern: in the placenta, CREB-1 and GATA-2 binding generates promoter activity in a cAMP-independent manner, while in ovarian cells, CREB-1 and GATA-4 are required for FSH responsiveness. However, as ovarian follicles advance toward ovulation, elevated Fra-2 expression replaces CREB-1 function by binding the same CRE1/2 motif. Our findings suggest that upon onset of follicular recruitment, CREB-1 mediates FSH/cAMP signaling, which switches to cAMP-independent expression of P450scc in luteinizing granulosa cells expressing Fra-2. In the placenta, the indispensable role of CREB-1 was demonstrated by use of dominant negative CREB-1 mutant, but neither cAMP nor Ser133 phosphorylation of CREB-1 are required for P450scc transcription. These observations suggest that placental regulation of P450scc expression is subjected to alternative signaling pathway(s) yet to be found.
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