P-TEFb inhibitors interfere with activation of p53 by DNA-damaging agents

• Published in: Oncogene Vol. 27; no. 9; pp. 1306 - 1309
• Main Authors: Radhakrishnan, S K, Bhat, U G, Halasi, M, Gartel, A L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.02.2008; Nature Publishing; Nature Publishing Group
• Subjects: Antimitotic agents; Antineoplastic agents; Antineoplastic Agents - antagonists & inhibitors; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Cancer; Cell Biology; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Chemical properties; Cisplatin; Clinical trials; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; DNA, Neoplasm - drug effects; Dosage and administration; Doxorubicin; Drug therapy; Flavonoids - pharmacology; Flavopiridol; Fundamental and applied biological sciences. Psychology; Genes, p53 - drug effects; Genetic aspects; Genetic transcription; GTP-binding protein; HCT116 Cells; Health aspects; Human Genetics; Humans; Inhibitor drugs; Internal Medicine; Medicine & Public Health; Molecular and cellular biology; Nucleosides - pharmacology; Oncology; Oncology, Experimental; p53 Protein; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Piperidines - pharmacology; Positive Transcriptional Elongation Factor B - antagonists & inhibitors; Protein binding; Pyrimidines - pharmacology; short-communication; Transcription elongation factor b; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; γ Radiation; United States; ARC; DNA-damaging agents; phosphorylation; flavopiridol; P-TEFb; p53; Antineoplastic agent; Phosphorylation; Activation; Carcinogenesis; TP53 Gene; Flavopiridol; DNA; Antiviral; Inhibitor; Tumor suppressor gene
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210737

Tumor suppressor p53 is stabilized in response to γ-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.