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

Oncogene volume 27, pages 1306–1309 (2008)Cite this article

Abstract

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.

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Acknowledgements

We thank Dr Sergei Nekhai for providing purified P-TEFb protein. This work was supported by the start-up funds from the UIC Department of Medicine, award from UIC Campus Research Board and by DOD Grant BC052816 to ALG.

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Author notes

  1. S K Radhakrishnan

    Present address: 4Current address: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.,

Authors and Affiliations

  1. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    S K Radhakrishnan, U G Bhat, M Halasi & A L Gartel

  2. Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA

    S K Radhakrishnan & A L Gartel

  3. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA

    M Halasi

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  1. S K Radhakrishnan
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Correspondence to A L Gartel.

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Radhakrishnan, S., Bhat, U., Halasi, M. et al. P-TEFb inhibitors interfere with activation of p53 by DNA-damaging agents. Oncogene 27, 1306–1309 (2008). https://doi.org/10.1038/sj.onc.1210737

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