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Classical anticytokinins do not interact with cytokinin receptors but inhibit cyclin-dependent kinases
Authors:Spíchal Lukás  Krystof Vladimír  Paprskárová Martina  Lenobel René  Styskala Jakub  Binarová Pavla  Cenklová Vera  De Veylder Lieven  Inzé Dirk  Kontopidis George  Fischer Peter M  Schmülling Thomas  Strnad Miroslav
Institution:Laboratory of Growth Regulators, Institute of Experimental Botany, AS CR and Palacky University, Slechtitel? 11, Olomouc, Czech Republic.
Abstract: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 pyrrolo2,3-d]pyrimidine and pyrazolo4,3-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.
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