Kotala V, Uldrijan S, Horky M, Trbusek M, Strnad M, Vojtesek B
Department of Experimental Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
Cell Mol Life Sci. 2001 Aug;58(9):1333-9. doi: 10.1007/PL00000944.
Activation of the p53 tumour suppressor protein by distinct forms of stress 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 tumour-derived cells. We analyzed the response of different human tumour 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 p21WAF1 induction, was observed in wildtype, but not mutant, p53-bearing tumour cells after treatment with roscovitine. The transcriptional activity of p53 was substantially higher in roscovitine-treated cells than in cells irradiated with ultraviolet C or ionizing radiation, even though all these agents induced a similar amount of p53 accumulation. These results highlight the therapeutic potential of roscovitine as an anticancer drug, especially in tumours retaining a functional wild-type p53 pathway.
不同形式的应激激活p53肿瘤抑制蛋白会通过诱导细胞周期停滞或凋亡来抑制细胞增殖。细胞周期蛋白依赖性激酶抑制剂罗斯考维汀已被证明可在人未转化细胞和肿瘤衍生细胞中诱导野生型p53的核积累。我们分析了不同人类肿瘤细胞系对罗斯考维汀治疗的反应及其p53状态。在用罗斯考维汀处理后，在携带野生型而非突变型p53的肿瘤细胞中观察到野生型p53蛋白的显著诱导以及p53依赖性转录的显著增强，这与p21WAF1的诱导相一致。尽管所有这些试剂诱导的p53积累量相似，但罗斯考维汀处理的细胞中p53的转录活性明显高于用紫外线C或电离辐射照射的细胞。这些结果突出了罗斯考维汀作为抗癌药物的治疗潜力，特别是在保留功能性野生型p53途径的肿瘤中。
