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J. Biol. Chem., Vol. 280, Issue 41, 34521-34529, October 14, 2005

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The Switch in Alternative Splicing of Cyclic AMP-response Element Modulator Protein CREM₂ (Activator) to CREM (Repressor) in Human Myometrial Cells Is Mediated by SRp40^*

Alison J. Tyson-Capper12, Jarrod Bailey, Adrian R. Krainer, Stephen C. Robson, and G. Nicholas Europe-Finner1

From the School of Surgical and Reproductive Sciences, 3rd Floor, William Leech Building, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724

The transcription factor cAMP-response element modulator (CREM) protein, 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 CREM₂, a potent transcriptional activator to the synthesis of CREM, 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 cAMP-response element-responsive target genes involved in uterine activity during gestation. We have investigated the splicing factors involved in controlling the expression of myometrial CREM splice variants. Data presented here from transient transfections indicate that the switch in the synthesis of CREM₂ to CREM 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 of how SRp40 regulates the switch in splicing from production of CREM₂ to CREM.

Received for publication, May 16, 2005 , and in revised form, June 30, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by Wellcome Trust Grant 066148.

² To whom correspondence should be addressed. Tel.: 44-191-222-8748; Fax: 44-191-222-5066; E-mail: A.J.Tyson-Capper{at}ncl.ac.uk.

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