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Pidd, a new death-domain–containing protein, is induced by p53 and promotes apoptosis

Nature Genetics volume 26, pages 122–127 (2000)Cite this article

Abstract

The p53 tumour suppressor promotes cell-cycle arrest or apoptosis in response to cellular stress, such as DNA damage and oncogenesis. This role of p53 is important for its tumour-suppression function1 and depends, at least in part, on its ability to bind to specific DNA sequences and activate the transcription of target genes2,3,4. The pathway through which p53 promotes apoptosis is not fully understood. Here we describe a new gene regulated by p53 that encodes a predicted protein of 915 amino acids in mice (910 amino acids in humans), which we have named Pidd. The mouse Pidd cDNA contains a p53 consensus DNA binding sequence upstream of the Pidd-coding region. This sequence element bound to p53 and conferred p53-dependent inducibility on a heterologous reporter gene. Moreover, Pidd RNA was induced by ionizing radiation in a p53-dependent manner and the basal level of Pidd RNA was dependent on Trp53 status. Overexpression of Pidd inhibited cell growth in a p53-like manner by inducing apoptosis. Antisense inhibition of Pidd expression attenuated p53-mediated apoptosis. Our data suggest that Pidd is an effector of p53-dependent apoptosis.

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Figure 1: p53 activates Pidd expression.
Figure 2: Sequence characterization of PIDD and sequence comparison.
Figure 3: The p53-consensus binding sequence in Pidd is responsive to p53.
Figure 4: Pidd suppresses tumour cell growth and induces apoptosis.
Figure 5: Apoptosis of mouse DP16.1/p53ts cells exposed to PIDD antisense (AS), sense (S) or mismatched (MM) oligonucleotides.

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Acknowledgements

We thank J. Manfredi for the p21-luciferase reporter construct; L. Donehower for Trp53−/− MEFs; and Y. Ben-David and R. Higgins for the purified, recombinant p53 protein. This work was supported by grants from the National Cancer Institute of Canada, the Medical Research Council of Canada and Amgen, Inc.

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  1. Ontario Cancer Institute/Princess Margaret Hospital and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Yunping Lin, Weili Ma & Samuel Benchimol

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Correspondence to Samuel Benchimol.

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Lin, Y., Ma, W. & Benchimol, S. Pidd, a new death-domain–containing protein, is induced by p53 and promotes apoptosis. Nat Genet 26, 122–127 (2000). https://doi.org/10.1038/79102

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