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J. Biol. Chem., Vol. 282, Issue 19, 14356-14363, May 11, 2007

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Classical Anticytokinins Do Not Interact with Cytokinin Receptors but Inhibit Cyclin-dependent Kinases^*

Luká Spíchal, Vladimír Krytof, Martina Paprskáová, René Lenobel¹, Jakub Stskala, Pavla Binarová, Vra Cenklová^¶, Lieven De Veylder^||, Dirk Inzé^||, George Kontopidis^**, Peter M. Fischer^**2, Thomas Schmülling, and Miroslav Strnad³

From the Laboratory of Growth Regulators, Institute of Experimental Botany, AS CR and Palack University, lechtitel 11, 783 71 Olomouc, Czech Republic, the Institute of Microbiology, AS CR, Vídeská 1083, 14220 Praha 4, Czech Republic, the ^¶Laboratory of Cell Biology and Cytoskeleton, Institute of Experimental Botany AS CR, Sokolovská 6, 772 00 Olomouc, Czech Republic, ^||Department of Plant Systems Biology, Flanders Institute for Biotechnology (VIB) and Department of Molecular Genetics, Ghent University, Technologiepark 927, B-9052 Gent, Belgium, ^**Cyclacel Limited, James Lindsay Place, Dundee DD1 5JJ, Scotland, United Kingdom, and the Free University of Berlin, Institute of Biology/Applied Genetics, Albrecht-Thaer-Weg 6, D-14195 Berlin, Germany

Cytokinins are a class of plant hormones that regulate the cell cycle and diverse developmental and physiological processes. Several compounds have been identified that antagonize the effects of cytokinins. Based on structural similarities and competitive inhibition, it has been assumed that these anticytokinins act through a common cellular target, namely the cytokinin receptor. Here, we examined directly the possibility that various representative classical anticytokinins inhibit the Arabidopsis cytokinin receptors CRE1/AHK4 (cytokinin response 1/Arabidopsis histidine kinase 4) and AHK3 (Arabidopsis histidine kinase 3). We show that pyrrolo[2,3-d]pyrimidine and pyrazolo[4,3-d]pyrimidine anticytokinins do not act as competitors of cytokinins at the receptor level. Flow cytometry and microscopic analyses revealed that anticytokinins inhibit the cell cycle and cause disorganization of the microtubular cytoskeleton and apoptosis. This is consistent with the hypothesis that they inhibit regulatory cyclin-dependent kinase (CDK) enzymes. Biochemical studies demonstrated inhibition by selected anti-cytokinins of both Arabidopsis and human CDKs. X-ray determination of the crystal structure of a human CDK2-anticytokinin complex demonstrated that the antagonist occupies the ATP-binding site of CDK2. Finally, treatment of human cancer cell lines with anticytokinins demonstrated their ability to kill human cells with similar effectiveness as known CDK inhibitors.

Received for publication, October 17, 2006 , and in revised form, February 7, 2007.

^* This work was supported by the Czech Ministry of Education Grant MSM 6198959216 (to M. S.) and MSMT-LC06034 (to M. S. and V. C.), Deutsche Forschungsgemeinschaft Grant Sfb 449 (to T. S.), the Volkswagenstiftung Grant I/76865 (to T. S. and M. S.), the Czech Science Foundation Grant 301/05/0418 (to M. S.), and the Grant Agency of the Czech Academy of Sciences Grant A5020302 (to P. B.) and Grant 204/07/1169 (to V. C.). 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 tables and figures as well as additional references.

¹ Present addresses: Max Planck Institute for Biochemistry, Department of Cell Biology, Am Klopferspitz 18a, D-82152 Martinsried, Germany.

² Present address: School of Pharmacy and Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.

³ To whom correspondence should be addressed: Miroslav Strnad, lechtitelù 11, CZ-78371 Olomouc, Czech Republic. Tel.: 420-58-5634850; Fax: 420-58-5634870; E-mail: miroslav.strnad{at}upol.cz.

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