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Direct coupling of the cell cycle and cell death machinery by E2F

Abstract

Unrestrained E2F activity forces S phase entry and promotes apoptosis through p53-dependent and -independent mechanisms. Here, we show that deregulation of E2F by adenovirus E1A, loss of Rb or enforced E2F-1 expression results in the accumulation of caspase proenzymes through a direct transcriptional mechanism. Increased caspase levels seem to potentiate cell death in the presence of p53-generated signals that trigger caspase activation. Our results demonstrate that mitogenic oncogenes engage a tumour suppressor network that functions at multiple levels to efficiently induce cell death. The data also underscore how cell cycle progression can be coupled to the apoptotic machinery.

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Figure 1: E1A induces caspases independently of ARF and p53.
Figure 2: Rb controls caspase expression.
Figure 3: Caspases display characteristics of E2F target-genes.
Figure 4: Caspase 7 is a direct E2F-1 target.
Figure 5: Loss of Rb sensitizes cells to apoptosis after cytochrome c release.

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Acknowledgements

We thank J. Nevins and K. Helin for E2F-1 expression vectors and L. Faleiro for contributions to the early stages of this work. We also thank J. Pelletier for helpful discussions, and E. de Stanchina and other members of the Lowe laboratory for encouragement and support. We thank J. Duffy for help in preparing the figures. This work was supported by Department of Defence Breast Cancer Research Program predoctoral fellowships (Z.N. and J.P.) and also by a programme project grant CA13106 from the National Cancer Institute (Y.L. and S.W.L.), and NIH-HG01696 from the National Institutes of Health (R.V.D. and M.Q.Z.). Z.N. is a DOD-BCRP fellow. S.W.L. is a Rita Allen Scholar.

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Correspondence to Scott W. Lowe.

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Nahle, Z., Polakoff, J., Davuluri, R. et al. Direct coupling of the cell cycle and cell death machinery by E2F. Nat Cell Biol 4, 859–864 (2002). https://doi.org/10.1038/ncb868

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