The switch in alternative splicing of cyclic AMP response element modulator protein CREM tau 2alpha (activator)to CREMalpha  (repressor) in human myometrial cells is mediated by SRp40

doi:10.1074/jbc.M505344200

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Papers In Press, published online ahead of print August 15, 2005
J. Biol. Chem, 10.1074/jbc.M505344200
Submitted on May 16, 2005
Revised on June 30, 2005
Accepted on August 15, 2005

The switch in alternative splicing of cyclic AMP response element modulator protein CREM $tau$ 2 $alpha$ (activator)to CREM $alpha$ (repressor) in human myometrial cells is mediated by SRp40

Alison J. Tyson-Capper, Jarrod Bailey, Adrian R. Krainer, Stephen C. Robson, and G. Nicholas Europe-Finner

Surgical & Reproductive Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH

Corresponding Author: A.J.Tyson-Capper{at}ncl.ac.uk

The transcription factor cAMP response element modulator protein, CREM, plays a major role in cAMP-responsive gene regulation. Biological consequences resulting from the transcriptional stimuli of CREM are dictated by the expression of multiple protein isoforms generated by extensive alternative splicing of its precursor mRNA. We have previously shown that alternative splicing enables the expression of the CREM gene to be ‘switched’ within the human myometrium during pregnancy from the production of CREM $tau$ $sub$ 2 $sub$ {alpha), a potent transcriptional activator to the synthesis of CREM $alpha$ , a transcriptional repressor. Furthermore we have recently reported that this change in the expression of CREM spliced variants is likely to have important ramifications on the regulation of downstream CRE-responsive target genes involved in uterine activity in gestation. We have investigated the splicing factors involved in controlling the expression of myometrial CREM splice variants. Data presented here from transient transfections indicates that the switch in the synthesis of CREM $tau$ $sub$ 2 $sub$ $alpha$ to CREM $alpha$ that occurs during pregnancy is regulated primarily by an SR protein family member, SRp40. We also show that expression of this splicing factor is tightly regulated in the myometrium during pregnancy. SRp40 regulates the splicing of CREM via its interactions with multiple ESE motifs present in the alternatively exons of CREM. In vitro splicing and electrophoretic mobility shift assays were employed to confirm the functionality of the SRp40-binding ESEs, thus providing a mechanistic explanation as to how SRp40 regulates the switch in splicing from production of CREM $tau$ $sub$ 2 $sub$ $alpha$ to CREM $alpha$ .

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The switch in alternative splicing of cyclic AMP response element modulator protein CREM 2(activator)to CREM (repressor) in human myometrial cells is mediated by SRp40

The switch in alternative splicing of cyclic AMP response element modulator protein CREM $tau$ 2 $alpha$ (activator)to CREM $alpha$ (repressor) in human myometrial cells is mediated by SRp40