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Role for the p53 homologue p73 in E2F-1-induced apoptosis

Nature volume 407, pages 645–648 (2000)Cite this article

Abstract

The transcription factor E2F-1 induces both cell-cycle progression and, in certain settings, apoptosis. E2F-1 uses both p53-dependent and p53-independent pathways to kill cells1,2,3,4,5,6,7,8. The p53-dependent pathway involves the induction by E2F-1 of the human tumour-suppressor protein p14ARF, which neutralizes HDM2 (human homologue of MDM2) and thereby stabilizes the p53 protein9. Here we show that E2F-1 induces the transcription of the p53 homologue p73. Disruption of p73 function inhibited E2F-1-induced apoptosis in p53-defective tumour cells and in p53-/- mouse embryo fibroblasts. We conclude that activation of p73 provides a means for E2F-1 to induce death in the absence of p53.

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Figure 1: E2F-1 induces p73 mRNA and protein accumulation.
Figure 2: The p73 promoter is E2F-responsive.
Figure 3: Modulation of p73 levels by physiological perturbants of E2F.
Figure 4: Validation of a dominant-negative p73 mutant. a, Representation of dominant-negative p73 mutant.
Figure 5: Inactivation of p73 inhibits E2F-1-induced apoptosis a, SAOS2 cells were transfected to produce wild-type E2F-1 or E2F-1(132E) in the presence or absence of increasing amounts of p73DD.

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Acknowledgements

We thank A. Yang and F. McKeon for p73+/- mice and K. Baker for help with the apoptosis assays. M.I. is an American Cancer Society postdoctoral fellow. W.G.K. is a Howard Hughes Medical Institute assistant investigator.

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Authors and Affiliations

  1. Dana-Farber Cancer Institute and Brigham and Womens Hospital, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Meredith Irwin, Maria Carmen Marin & William G. Kaelin Jr

  2. Regulation of Cell Growth Laboratory, NCI-FCRDC, Frederick, 21702, Maryland, USA

    Andrew C. Phillips & Karen H. Vousden

  3. Department of Laboratory Medicine and Pathology, Mayo Clinic/ Mayo Medical School, Rochester, 55905, Minnesota, USA

    Ratnam S. Seelan, David I. Smith & Wanguo Liu

  4. Department of Biology and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge , 02139, Massachusetts, USA

    Elsa R. Flores, Kenneth Y. Tsai & Tyler Jacks

  5. Howard Hughes Medical Institute, Chevy Chase, 20185-6789, Maryland, USA

    Elsa R. Flores, Tyler Jacks & William G. Kaelin Jr

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  1. Meredith Irwin
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Correspondence to William G. Kaelin Jr.

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Irwin, M., Marin, M., Phillips, A. et al. Role for the p53 homologue p73 in E2F-1-induced apoptosis. Nature 407, 645–648 (2000). https://doi.org/10.1038/35036614

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