P-TEFb inhibitors interfere with activation of p53 by DNA-damaging agents
P-TEFb inhibitors interfere with activation of p53 by DNA-damaging agents
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DOI：
10.1038/sj.onc.1210737
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发表时间：
2008-02-21
期刊：
影响因子：
8
通讯作者：
Gartel, A. L.
中科院分区：
文献类型：
--
作者：
Radhakrishnan, S. K.;Bhat, U. G.;Gartel, A. L.
肿瘤抑制基因P53在c-射线或DNA损伤剂治疗后稳定下来，结果是P53转录激活其靶点，导致细胞周期停滞或细胞凋亡。4-氨基-6-肼-7-b-d-呋喃核糖-7H-吡咯并[2，3-d]-嘧啶-5-甲酰胺(ARC)等P-TEFb(阳性转录延伸因子b)抑制剂可上调p53蛋白水平，但抑制其靶标p21和Hdm2的表达。DNA损伤剂阿霉素和顺铂与P-TEFb抑制剂黄吡啶联合使用，用于治疗一些癌症患者的临床试验。在本研究中，我们发现P-TEFb抑制剂阻断了阿霉素诱导的P53的磷酸化。此外，P-TEFb抑制剂与阿霉素联合处理细胞可抑制阿霉素诱导的P53与DNA的结合和P53的转录活性。这些数据表明，在携带野生型p53的肿瘤中，P-TEFb抑制剂可能拮抗DNA损伤剂对p53的激活。
Tumor suppressor p53 is stabilized in response to c-irradiation or treatment with DNA-damaging agents, and as a result p53 transcriptionally activates its targets leading to cell-cycle arrest or apoptosis. P-TEFb (positive transcription elongation factor b) inhibitors such as flavopiridol or 4-amino-6-hydrazino-7-b-d-ribofuranosyl-7H- pyrrolo[2,3-d]-pyrimidine-5-carboxamide (ARC) upregulate p53 protein levels, but inhibit the expression of its targets p21 and hdm2. DNA-damaging agents, doxorubicin and cisplatin are being used in combination with P-TEFb inhibitor flavopiridol in clinical trials for the treatment of some cancer patients. In this study, we found that P-TEFb inhibitors block the phosphorylation of p53 induced by doxorubicin. Furthermore, treatment of cells with P-TEFb inhibitors together with doxorubicin inhibits doxorubicin-induced binding of p53 to DNA and p53 transcriptional activity. These data suggest that P-TEFb inhibitors may antagonize the activation of p53 by DNA-damaging agents in tumors with wild-type p53.