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Role of the p53-homologue p73 in E2F1-induced apoptosis

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 57). 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.

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Figure 1: Induction of p73 by E2F1.
Figure 2: Transcriptional activation of the human TP73 promoter by E2F1.
Figure 3: Induction of p53-responsive targets by E2F1.
Figure 4: Inhibition of E2F1-induced p73 function.
Figure 5: Inhibition of E2F1-induced p73 function by the tumour-derived p53 mutant R175H.
Figure 6: Reduction of E2F1-induced apoptosis by inhibition of p73.

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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.).

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Correspondence to Brigitte M. Pützer.

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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

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