The cell division kinases (CDKs) have diverse functions, most of which are prominently linked to the control of cells division and/or transcription. Our laboratory identified a novel CDK subfamily, the CDK11 protein kinases previously known as the PITSLRE kinases. Cyclin L1 and, more recently, cyclin L2, are regulatory partners of the CDK 11 isoforms. We determined that the CDK11p110 isoform is a component of RNA polymerase II (RNAP II) complexes, consistent with its demonstrated ability to influence transcriptional elongation and potentially transcriptional initiation via interaction with a novel RNA-binding motif protein RBM16. CDK11p110 is also found in spliceosome complexes and has a role in pre-mRNA splicing events. This function is unique among the CDKs, with the RS-rich general pre-mRNA splicing factors RNPS1 and 9G8 identified as bona fide interactors. CDK11p110/p58-null mouse embryos fail to develop past E3.5, indicating that CDK11p110 and/or CDK11p58 kinase function is essential for post-blastocyst embryonic development. Taken together, these studies strongly suggest that CDK11p110 kinase function is essential for normal regulation of transcription and RNA processing during the cell cycle. However, we do not know how CDK11p110 kinase function might coordinately regulate the composition/function of RNAP II/spliceosome complexes. Based upon our cdc2l gene knockout studies CDK11p110/p58 is essential for normal embryonic development, unlike other CDKs (i.e., with the exception of CDKs-1 and -3), we hypothesize that a portion of the phenotype of these knockout mice is due to the absence of CDK11p110 and that the functions of the protein are required for development. To test these hypotheses we propose experiments to answer the following specific aims: (1) What is the functional significance of CDK11p110 kinase association with and/or phosphorylation of factors in RNAPII and spliceosome complexes? Does CDK11p110 play a crucial role in coordinating splicing and transcription? (2) What is the function of the CK11p110 isoform in the developing embryo? Is it possible to obtain viable embryos if only CDK11p110 or CDK11 is ablated? If so, are these mice more prone to tumors or developmental defects?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Cell Development and Function Integrated Review Group (CDF)
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Bender, Michael T
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St. Jude Children's Research Hospital
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Loyer, Pascal; Busson, Adeline; Trembley, Janeen H et al. (2011) The RNA binding motif protein 15B (RBM15B/OTT3) is a functional competitor of serine-arginine (SR) proteins and antagonizes the positive effect of the CDK11p110-cyclin L2? complex on splicing. J Biol Chem 286:147-59
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Li, Tongyuan; Inoue, Akira; Lahti, Jill M et al. (2004) Failure to proliferate and mitotic arrest of CDK11(p110/p58)-null mutant mice at the blastocyst stage of embryonic cell development. Mol Cell Biol 24:3188-97
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