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hAda3 regulates p14ARF-induced p53 acetylation and senescence

Oncogene volume 26, pages 6261–6268 (2007)Cite this article

Abstract

Acetylation is thought to be a key event for p53 activation. We demonstrate that p14ARF-induced senescence of human mammary epithelial cells (MEC) is associated with p53 acetylation and requires hAda3, a component of histone acetyltransferase complexes and a p53 transcriptional coactivator. Expression of the N-terminal domain of hAda3 that binds p53 but not p300 blocked p14ARF-induced p53 acetylation and protected MECs from senescence. Consistent with these findings, the human papillomavirus 16 E6 mutant Y54D, which selectively targets hAda3 but not p53 for degradation and protects MECs from p14ARF-induced senescence, inhibited p53 acetylation. In H1299 cells, hAda3 overexpression increased p300-mediated p53 acetylation, which conversely decreased following small interfering RNA (siRNA) knockdown of hAda3. Moreover, depletion of hAda3 by siRNA inhibited endogenous p53 acetylation and accumulation of p21cip1 in response to ectopic p14ARF. These studies reveal that, in addition to its known ability to inhibit Mdm2-mediated p53 degradation, p14ARF signals through hAda3 to stimulate p53 acetylation and the induction of cell senescence.

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Acknowledgements

We thank Rainer Brachmann and Steven Grossman for generously providing plasmids, Yuval Nitzan for help with computer graphics, Jason Chen and Samisubbu Naidu for review of the manuscript. We appreciate the assistance of Ting Yu with confocal microscopy. This work was supported by NIH grant R01CA107394.

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Author notes

  1. P Sekaric and V A Shamanin: These two authors contributed equally to the work.

Authors and Affiliations

  1. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    P Sekaric, V A Shamanin & E J Androphy

  2. Institute of Cytology and Genetics, Novosibirsk, Russia

    V A Shamanin

  3. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA

    J Luo

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  1. P Sekaric
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  2. V A Shamanin
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  3. J Luo
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  4. E J Androphy
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Corresponding author

Correspondence to E J Androphy.

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Addendum

While this manuscript was under review, another study reported the role of hADA3 in DNA damage-induced acetylation and stabilization of the p53 protein (Nag et al., 2007).

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Sekaric, P., Shamanin, V., Luo, J. et al. hAda3 regulates p14ARF-induced p53 acetylation and senescence. Oncogene 26, 6261–6268 (2007). https://doi.org/10.1038/sj.onc.1210462

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