Abstract
The adenovirus E1A and SV40 large-T-antigen oncoproteins bind to members of the p300/CBP transcriptional coactivator family. Binding of p300/CBP is implicated in the transforming mechanisms of E1A and T-antigen oncoproteins. A common region of the T antigen is critical for binding both p300/CBP and the tumour suppressor p53 (ref. 1), suggesting a link between the functions of p53 and p300. Here we report that p300/CBP binds to p53 in the absence of viral oncoproteins, and that p300 and p53 colocalize within the nucleus and coexist in a stable DNA-binding complex. Consistent with its ability to bind to p300, E1A disrupted functions mediated by p53. It reduced p53-mediated activation of the p21 and bax promoters, and suppressed p53-induced cell-cycle arrest and apoptosis. We conclude that members of the p300/CBP family are transcriptional adaptors for p53, modulating its checkpoint function in the G1 phase of the cell cycle and its induction of apoptosis. Disruption of p300/p53-dependent growth control may be part of the mechanism by which E1A induces cell transformation. These results help to explain how p53 mediates growth and checkpoint control, and how members of the p300/CBP family affect progression from G1 to the S phase of the cell cycle.
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Acknowledgements
We thank everyone who provided reagents used in this study; J. Kahana, P. Silver, C. Jost and W. G. Kaelin Jr for providing unpublished reagents; P. Adams, R. Eckner, M. Ewen, O. Iliopoulos, R. Scully, T.-P. Yao and members of the Division of Neoplastic Disease Mechanisms for discussions; M.Modabber for graphics; and M. Simone for flow cytometry. This work was supported by grants from the American Cancer Society (N.L.L.), the Howard Hughes Medical Institute (S.R.G.), The Cancer Research Fund of the Damon Runyon–Walter Winchell Foundation (D.G.), the Dana-Farber/Sandoz Drug Discovery Program, and the National Cancer Institute (J. DeC. and D.M.L.).
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Lill, N., Grossman, S., Ginsberg, D. et al. Binding and modulation of p53 by p300/CBP coactivators. Nature 387, 823–827 (1997). https://doi.org/10.1038/42981
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DOI: https://doi.org/10.1038/42981
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