Functional p53 in cells contributes to the anticancer effect of the cyclin-dependent kinase inhibitor roscovitine

0335831 - ÚEB 2010 RIV US eng J - Journal Article
Paprskářová, Martina - Kryštof, Vladimír - Jorda, Radek - Džubák, P. - Hajdúch, M. - Wesierska-Gadek, J. - Strnad, Miroslav
Functional p53 in cells contributes to the anticancer effect of the cyclin-dependent kinase inhibitor roscovitine.
[Funkční p53 v buňkách přispívá k protinádorovému účinku roskovitinu.]
Journal of Cellular Biochemistry. Roč. 107, č. 3 (2009), s. 428-437. ISSN 0730-2312. E-ISSN 1097-4644
R&D Projects: GA ČR GA204/08/0511
Institutional research plan: CEZ:AV0Z50380511
Keywords : APOPTOSIS * CYCLIN-DEPENDENT KINASE * OLOMOUCINE II * p53
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 2.935, year: 2009

To define the role of p53 in the anticancer effect of selective CDK inhibitors, two related compounds roscovitine and olomoucine II were studied. Roscovitine differs functionally from its congener olomoucine II only in the selectivity towards transcriptional CDK9. Action of both compounds on proliferation, cell cycle progression and apoptosis was examined in RPMI-8226 cells expressing the temperature-sensitive mutant of p53 and in MCF-7 cells with wild-type p53. Both compounds blocked proliferation, decreased phosphorylation of RNA polymerase II, downregulated anti-apoptotic protein Mcl-1 in both cell lines in a dose-dependent manner, and also activated p53 in MCF-7 cells. Moreover, we showed that the anticancer efficiency of CDK inhibitors was enhanced by active p53 in RPMI-8226 cells kept at permissive temperature, where downregulation of Mcl-1, fragmentation of PARP-1 and increased caspase-3 activity was detected with lower doses of the compounds.

Inhibitory CDK působí na transformované buňky několika různými mechanismy. Mimo jiné jsou schopny ovlivňovat hladinu nádorového supresoru p53 a aktivovat jeho transkripční schopnosti. Pro zjištění vlivu p53 na protinádorový účinek roskovitinu jsme porovnávali roskovitin s olomoucinem II, velmi příbuzným inhibitorem CDK s odlišnou strukturou. Výsledky naznačují, že za shcopnostní akumulovat p53 v buňkách stojí jeho inhibitční aktivita vůči CDK9.
Permanent Link: http://hdl.handle.net/11104/0180191