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Classical anticytokinins do not interact with cytokinin receptors but inhibit cyclin-dependent kinases
Spíchal L, Krystof V, Paprskárová M, Lenobel R, Styskala J, Binarová P, Cenklová V, De Veylder L, Inzé D, Kontopidis G, Fischer PM, Schmülling T, Strnad M
Jazyk angličtina Země Spojené státy americké
E-zdroje NLK Online
Freely Accessible Science Journals od 1905 do Před 1 rokemPubMed Central od 2005
Europe PubMed Central od 2005 do Před 1 rokem
Open Access Digital Library od 1905-10-01
Open Access Digital Library od 1905-10-01
Elsevier Open Access Journals od 1905
ROAD: Directory of Open Access Scholarly Resources od 1905
- MeSH
- apoptóza MeSH
- Arabidopsis metabolismus MeSH
- buněčný cyklus MeSH
- chronická myeloidní leukemie metabolismus patologie MeSH
- cyklin-dependentní kinasa 2 antagonisté a inhibitory metabolismus MeSH
- cytokininy antagonisté a inhibitory metabolismus MeSH
- cytoskelet MeSH
- financování organizované MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- nádorové buňky kultivované MeSH
- nádory kostí metabolismus patologie MeSH
- nádory prsu metabolismus patologie MeSH
- osteosarkom metabolismus patologie MeSH
- proliferace buněk účinky léků MeSH
- proteinkinasy metabolismus MeSH
- proteiny huseníčku metabolismus MeSH
- průtoková cytometrie MeSH
- pyrimidiny farmakologie MeSH
- receptory buněčného povrchu metabolismus MeSH
- regulace genové exprese u rostlin MeSH
- transportní proteiny MeSH
- Check Tag
- lidé MeSH
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.
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- $a 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.
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