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J. Biol. Chem., Vol. 279, Issue 32, 33727-33741, August 6, 2004

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Identification of Interaction Partners and Substrates of the Cyclin A1-CDK2 Complex^*

Sven Diederichs, Nicole Bäumer, Ping Ji, Stephan K. Metzelder, Gregory E. Idos, Thomas Cauvet, Wenbing Wang, Maria Möller, Sarah Pierschalski, Jörg Gromoll¶, Mark G. Schrader||, H. Phillip Koeffler, Wolfgang E. Berdel, Hubert Serve, and Carsten Müller-Tidow**

From the Department of Medicine, Hematology/Oncology, and the ^¶Institute of Reproductive Medicine, University of Münster, D-48129 Münster, Germany, the Division of Hematology/Oncology, Cedars-Sinai Research Institute/UCLA School of Medicine, Los Angeles, California 90048, and the ^||Department of Urology, University Hospital Benjamin Franklin, D-12200 Berlin, Germany

The CDK2-associated cyclin A1 is essential for spermatogenesis and contributes to leukemogenesis. The detailed molecular functions of cyclin A1 remain unclear, since the molecular networks involving cyclin A1-CDK2 have not been elucidated. Here, we identified novel cyclin A1/CDK2 interaction partners in a yeast triple-hybrid approach. Several novel proteins (INCA1, KARCA1, and PROCA1) as well as the known proteins GPS2 (G-protein pathway suppressor 2), Ku70, receptor for activated protein kinase C1/guanine nucleotide-binding protein -2-like-1, and mRNA-binding motif protein 4 were identified as interaction partners. These proteins link the cyclin A1-CDK2 complex to diverse cellular processes such as DNA repair, signaling, and splicing. Interactions were confirmed by GST pull-down assays and co-immunoprecipitation. We cloned and characterized the most frequently isolated unknown gene, which we named INCA1 (inhibitor of CDK interacting with cyclin A1). The nuclear INCA1 protein is evolutionarily conserved and lacks homology to any known gene. This novel protein and two other interacting partners served as substrates for the cyclin A1-CDK2 kinase complex. Cyclin A1 and all interaction partners were highly expressed in testis with varying degrees of tissue specificity. The highest expression levels were observed at different time points during testis maturation, whereas expression levels in germ cell cancers and infertile testes decreased. Taken together, we identified testicular interaction partners of the cyclin A1-CDK2 complex and studied their expression pattern in normal organs, testis development, and testicular malignancies. Thereby, we establish a new basis for future functional analyses of cyclin A1. We provide evidence that the cyclin A1-CDK2 complex plays a role in several signaling pathways important for cell cycle control and meiosis.

Received for publication, February 17, 2004 , and in revised form, April 29, 2004.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) NM_213726, NP_998891, AY601906, AY601907, AY601909–AY601912, AY601914, AY601916, AAT09152ndash;AAT09159.

^* This work was supported by Deutsche Krebshilfe Grant 10-1539-Mü2, Deutsche José-Carreras-Leukämie-Stiftung, Deutsche Forschungsge-meinschaft (DFG) Grants Mu1328/2-3 and SF293A15, and IZKF at the University of Münster Grants IZKF Mül2/096/04 and Ser2/041/04. 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 one additional figure and three additional tables.

^** Supported by DFG Heisenberg Program Grant Mu1328/3-1. To whom correspondence should be addressed: Dept. of Medicine, Hematology/Oncology, University of Münster, Domagkstrasse 3, D-48129 Münster, Germany. Tel.: 49-251-835-6229; Fax: 49-251-835-2673; E-mail: muellerc{at}uni-muenster.de.

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