Abstract
Most human cancers harbour aberrations of cell-cycle control1, which result in deregulated activity of the E2F transcription factors with concomitant enhanced cell-cycle progression2. Oncogenic signalling by E2F1 has recently been linked to stabilization and activation of the tumour suppressor p53 (refs 1,3,4). The p73 protein shares substantial sequence homology and functional similarity with p53 (refs 5–7). Hence, several previously considered p53-independent cellular activities may be attributable to p73. Here we provide evidence that E2F1 directly activates transcription of TP73, leading to activation of p53-responsive target genes and apoptosis. Disruption of p73 function by a tumour-derived p53 mutant reduced E2F1-mediated apoptosis. Thus, p73 activation by deregulated E2F1 activity might constitute a p53-independent, anti-tumorigenic safeguard mechanism.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Sherr, C.J. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 12, 2984–2991 (1998).
Phillips, A.C., Bates, S., Ryan, K.M., Helin, K. & Vousden, K.H. Induction of DNA synthesis and apoptosis are separable functions of E2F-1. Genes Dev. 11, 1853–1863 ( 1998).
Bates, S. et al. p14ARF links the tumor suppressors RB and p53. Nature 395, 124–125 ( 1998).
Zindy, F. et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12, 2424–2433 (1998).
Kaghad, M. et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809–819 ( 1997).
Jost, C.A., Marin, M.C. & Kaelin, W.G. p73 is a human p53-related protein that can induce apoptosis. Nature 389, 191– 194 (1997).
Zhu, J., Jiang, J., Zhou, W. & Chen, X. The potential tumor suppressor p73 differentially regulates cellular p53 target genes. Cancer Res. 58, 5061–5068 (1998).
Vigo, E. et al. CDC25A phosphatase is a target of E2F and is required for efficient E2F-induced S phase. Mol. Cell. Biol. 19, 6379–6395 (1999).
Zeng, X. et al. The N-terminal domain of p73 interacts with the CH1 domain of p300/CREB binding protein and mediates transcriptional activation and apoptosis. Mol. Cell. Biol. 20, 1299–1310 (2000).
Di Como, C.J., Gaiddon, C. & Prives, C. p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol. Cell. Biol. 19 , 1438–1449 (1999).
Marin, M.C. et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nature Genet. 25, 47– 54 (2000).
Phillips, A.C. et al. E2F-1 potentiates cell death by blocking anti-apoptotic signaling pathways. Mol. Cell 4, 771– 781 (1999).
Kovalev, S. et al. Expression level, allelic origin, and mutation analysis of the p73 gene in neuroblastoma tumors and cell lines. Cell Growth Differ. 9, 897–903 ( 1998).
Yokomizo, A. et al. Overexpression of the wild type p73 gene in human bladder cancer. Oncogene 18, 1625– 1629 (1999).
Ng, S.-W. et al. Analysis of p73 in human borderline and invasive ovarian tumor . Oncogene 19, 1885–1890 (2000).
Helin, K., Harlow, E. & Fattaey, A. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein. Mol. Cell. Biol. 13, 6501–6508 (1993).
Cress, W.D., Johnson, D.G. & Nevins, J.R. A genetic analysis of the E2F1 gene distinguishes regulation by Rb, p107, and adenovirus E4. Mol. Cell. Biol. 13, 6314–6325 (1993).
Lee, T.A. & Farnham, P.J. Exogenous E2F expression is growth inhibitory before, during, and after cellular transformation. Oncogene 19, 2257–2268 ( 2000).
Baker, S.J., Markowitz, S., Fearon, E., Willson, B. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249 , 912–915 (1990).
DeLaurenzi, V. et al. Two new p73 splice variants, γ and δ, with different transcriptional activity. J. Exp. Med. 188, 1763–1768 (1998).
Pützer, B.M., Stiewe, T., Crespo, F. & Esche, H. Improved safety through tamoxifen-regulated induction of cytotoxic genes delivered by Ad vectors for cancer gene therapy. Gene Ther. 7 , 1317–1325 (2000).
Kalejta, R.F., Shenk, T. & Beavis, A.J. Use of a membrane-localized green fluorescent protein allows simultaneous identification of transfected cells and cell cycle analysis by flow cytometry. Cytometry 29, 286–291 (1997).
de Stanchina, E. et al. E1A signaling to p53 involves the p19ARF tumor suppressor . Genes Dev. 12, 2434–2442 (1998).
Van den Hoff, M.J.B., Moorman, A.F.M. & Lamers, W.H. Electroporation intracellular buffer increases cell survival. Nucleic Acids Res. 20, 2902 (1992).
Chiang, S.-Y., Azizkhan, J.C. & Beerman, T.A. A comparison of DNA-binding drugs as inhibitors of E2F1- and Sp1-DNA complexes and associated gene expression. Biochemistry 37, 3109–3115 (1998).
Wu, K.-J. et al. Direct activation of TERT transcription by c-MYC. Nature Genet. 21, 220–224 (1999).
Marin, M.C. et al. Viral oncoproteins discriminate between p53 and the p53 homolog p73. Mol. Cell. Biol. 18, 6316– 6324 (1998).
Ormerod, M.G., Sun, X.-M., Brown, D., Snowden, R.T. & Cohen, G.M. Quantification of apoptosis and necrosis by flow cytometry. Acta Oncol. 32, 417–424 (1993).
Acknowledgements
We thank S. Zimmermann for technical assistance; H. Karsunky for preparing mouse embryo fibroblasts; K. Lennartz for assistance with flow cytometry; and K. Helin, J.R. Nevins, P. Farnham, B. Vogelstein, G. Melino, H. Lu and S. Lowe for providing expression plasmids for E2F1, ER-E2F1, E132 mutant, E2F1-E138/GFP, p53 R175H, p73 and the pLPC retroviral vector, respectively. This work was supported in part by a grant of the Deutsche Krebshilfe, Dr. Mildred Scheel Stiftung (B.M.P.) and the University of Essen, IFORES program of the Medical Faculty (T.S.).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Stiewe, T., Pützer, B. Role of the p53-homologue p73 in E2F1-induced apoptosis. Nat Genet 26, 464–469 (2000). https://doi.org/10.1038/82617
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/82617
This article is cited by
-
Silencing of TP73-AS1 impairs prostate cancer cell proliferation and induces apoptosis via regulation of TP73
Molecular Biology Reports (2022)
-
Context-dependent activation of p53 target genes and induction of apoptosis by actinomycin D in aerodigestive tract cancers
Apoptosis (2022)
-
The p53 family member p73 in the regulation of cell stress response
Biology Direct (2021)
-
BCL11B suppresses tumor progression and stem cell traits in hepatocellular carcinoma by restoring p53 signaling activity
Cell Death & Disease (2020)
-
Programmed expression of pro-apoptotic BMCC1 during apoptosis, triggered by DNA damage in neuroblastoma cells
BMC Cancer (2019)