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J. Biol. Chem., Vol. 283, Issue 12, 7721-7732, March 21, 2008

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Characterization of Cyclin L1 and L2 Interactions with CDK11 and Splicing Factors

INFLUENCE OF CYCLIN L ISOFORMS ON SPLICE SITE SELECTION^*

Pascal Loyer¹, Janeen H. Trembley¹, Jose A. Grenet, Adeline Busson², Anne Corlu, Wei Zhao^¶, Mehmet Kocak^¶, Vincent J. Kidd, and Jill M. Lahti³

From the INSERM U522 Régulation des Equilibres Fonctionnels du Foie Normal et Pathologique, IFR140, Université de Rennes 1, Hôpital Pontchaillou, 35033 Rennes, France and the Departments of Genetics and Tumor Cell Biology and ^¶Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105

Although it has been reported that cyclin L1 and L2 proteins interact with CDK11^p110, the nature of the cyclin L transcripts, the formation of complexes between the five cyclin L and the three CDK11 protein isoforms, and the influence of these complexes on splicing have not been thoroughly investigated. Here we report that cyclin L1 and L2 genes generate 14 mRNA variants encoding six cyclin L proteins, one of which has not been described previously. Using cyclin L gene-specific antibodies, we demonstrate expression of multiple endogenous cyclin L proteins in human cell lines and mouse tissues. Moreover, we characterize interactions between CDK11^p110, mitosis-specific CDK11^p58, and apoptosis-specific CDK11^p46 with both cyclin L and -β proteins and the co-elution of these proteins following size exclusion chromatography. We further establish that CDK11^p110 and associated cyclin L/β proteins localize to splicing factor compartments and nucleoplasm and interact with serine/arginine-rich proteins. Importantly, we also determine the effect of CDK11-cyclin L complexes on pre-mRNA splicing. Preincubation of nuclear extracts with purified cyclin L and -β isoforms depletes the extract of in vitro splicing activity. Ectopic expression of cyclin L1, L1β, L2, or L2β or active CDK11^p110 individually enhances intracellular intron splicing activity, whereas expression of CDK11^p58/p46 or kinase-dead CDK11^p110represses splicing activity. Finally, we demonstrate that expression of cyclins L and -β and CDK11^p110 strongly and differentially affects alternative splicing in vivo. Together, these data establish that CDK11^p110 interacts physically and functionally with cyclin L and -β isoforms and SR proteins to regulate splicing.

Received for publication, October 2, 2007 , and in revised form, January 18, 2008.

^* This work was supported in part by National Institutes of Health Grant R01GM044088, the American Lebanese Syrian Associated Charities, Cancer Center Support Grant P30CA021765, and INSERM. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental "Experimental Procedures," additional reference, Table 1, and Data 1–6.

¹ Both authors contributed equally to this work.

² Recipient of a doctoral fellowship from the Ligue Contre le Cancer (Comité Départemental des Côtes d'Armor, 22, France).

³ To whom correspondence should be addressed: Dept. of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105. Tel.: 901-495-3597; Fax: 901-495-2381; E-mail: Jill.Lahti{at}stjude.org.

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