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PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression

Nature volume 422, pages 527–531 (2003)Cite this article

Abstract

p53 has a role in many cellular processes through the transcriptional regulation of target genes1,2. PAC1 (phosphatase of activated cells 1; also known as dual specificity phosphatase 2, DUSP2) is a dual threonine/tyrosine phosphatase that specifically dephosphorylates and inactivates mitogen-activated protein (MAP) kinases3,4. Here we show that during apoptosis, p53 activates transcription of PAC1 by binding to a palindromic site in the PAC1 promoter. PAC1 transcription is induced in response to serum deprivation and oxidative stress, which results in p53-dependent apoptosis, but not in response to γ-irradiation, which causes cell cycle arrest5,6. Reduction of PAC1 transcription using small interfering RNA inhibits p53-mediated apoptosis, whereas overexpression of PAC1 increases susceptibility to apoptosis and suppresses tumour formation. Moreover, activation of p53 significantly inhibits MAP kinase activity. We conclude that, under specific stress conditions, p53 regulates transcription of PAC1 through a new p53-binding site, and that PAC1 is necessary and sufficient for p53-mediated apoptosis. Identification of a palindromic motif as a p53-binding site may reveal a novel mechanism whereby p53 regulates its target genes.

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Figure 1: Transcriptional regulation of PAC1 by p53.
Figure 2: Transactivation of the PAC1 promoter by p53.
Figure 3: Physical interaction between p53 and a palindromic site in the PAC1 promoter.
Figure 4: Requirement of PAC1 for p53-mediated apoptosis.

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Acknowledgements

We thank A. J. Levine for advice on promoter studies and for providing critical reagents, and W. Gu for the pCMV-p53Δ270 plasmid. We are grateful to H. B. Lieberman for critical reading of the manuscript. We also thank T. A. Sato for help with the luciferase assay. This work was supported by a start up fund from the Columbia University (Y.Y.) and NIH grants (to Y.Y. and E.J.H).

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Authors and Affiliations

  1. Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, New York, 10032, USA

    Yuxin Yin, Yu-Xin Liu, Yan J. Jin & Eric J. Hall

  2. Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute, NIH, 31 Center Drive, Bethesda, Maryland, 20892, USA

    J. Carl Barrett

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Correspondence to Yuxin Yin.

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Yin, Y., Liu, YX., Jin, Y. et al. PAC1 phosphatase is a transcription target of p53 in signalling apoptosis and growth suppression. Nature 422, 527–531 (2003). https://doi.org/10.1038/nature01519

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