Vliv syntetickych inhibitoru cyklin-dependentnich kinaz na stabilitu a aktivitu proteinu p53 v nadorove bunce.

Abstract

The loss of the p53 tumor suppressor protein function is the most commont event leading to the development of cancer. In normal cells, p53 is present at low levels because the protein is rapidly degraded by the ubiquitin-mediated proteasome pathway following synthesis. Stress induced signals inhibit p53 degradation, leading to rapid stabilization and accumulation of p53 protein in the cell, and followed by p53 protein activation by mechanisms including phosphorylation and acetylation. Such activation of the p53 protein leads to inhibition of cellular proliferation by inducing cell cycle arrest or apoptosis. The cyclin-dependent kinase inhibitor roscovitine has been shown to induce nuclear accumulation of wild-type p53 in human untransformed and tumor-derived cells. We analyzed the response of different human tumor cell lines to roscovitine-treatment with respect to their p53 status. Striking induction of wild-type p53 protein and dramatic enhancement of p53-dependent transcription, coinciding with p21WAFI protein induction, was observed in wild-type, but not mutant, p53-bearing tumor cells after treatment with roscovitine.The transcriptional activity of p53 protein was tested using Arn8 cells bearing a stably integrated beta-galactosidase gene containing a consensus p53-binding site in its promoter. The ability of p53 to transactivate beta-galactosidase expression was substantially higher in roscovitine-treated cells than in cells irradiated with UV-C or ionizing radiation, even though all these agents induced a similar amount of p53 accumulation. The cotreatment of cells with roscovitine and DNA-damaging agents lead to further strong increase of p53 transcriptional activity in Arn8 melanoma cells.Available from STL Prague, CZ / NTK - National Technical LibrarySIGLECZCzech Republi