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Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis

Oncogene volume 24, pages 627–636 (2005)Cite this article

Abstract

The tumor suppressor protein p53 regulates transcription of many genes that mediate cell cycle arrest, apoptosis, DNA repair and other cellular responses. Here we show that Ipaf, a human CED-4 homologue and an activator of caspase-1, is induced by p53. Overexpression of p53 by transfection in U2OS and A549 cells increased Ipaf mRNA levels. Treatment of p53-positive cell lines U2OS and MCF-7 with the DNA damaging drug, doxorubicin, which increases p53 protein level, induced expression of Ipaf mRNA but similar treatment of MCF-7-mp53 (a clone of MCF-7 cells expressing mutant p53) and p53-negative K562 cells showed much less induction of Ipaf gene expression. Expression analysis for Ipaf mRNA in doxorubicin-treated human tumor cell lines suggests that p53-dependent as well as p53-independent mechanisms are involved in the regulation of Ipaf gene expression in a cell-type-specific manner. The Ipaf promoter was activated by normal p53 but not by His273 mutant of p53. A functional p53-binding site was identified in the Ipaf promoter. A dominant-negative mutant of Ipaf inhibited p53-induced and doxorubicin-induced apoptosis by about 50%. Ipaf-directed small hairpin RNA downregulated p53-induced Ipaf gene expression and also reduced p53-induced apoptosis. Doxorubicin-induced apoptosis was also inhibited by Ipaf-directed small hairpin RNA. Our results show that p53 can directly induce Ipaf gene transcription, which contributes to p53-dependent apoptosis in at least some human cells.

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Acknowledgements

This work was supported by a grant from the Council of Scientific and Industrial Research, Government of India to GS. SS gratefully acknowledges the University Grants Commission, India for a senior research fellowship.

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Authors and Affiliations

  1. Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad, 500 007, India

    Subhashini Sadasivam, Sanjeev Gupta, Vegesna Radha & Ghanshyam Swarup

  2. Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, 560 064, India

    Kiran Batta & Tapas K Kundu

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  1. Subhashini Sadasivam
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  2. Sanjeev Gupta
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  3. Vegesna Radha
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  4. Kiran Batta
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Correspondence to Ghanshyam Swarup.

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Sadasivam, S., Gupta, S., Radha, V. et al. Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis. Oncogene 24, 627–636 (2005). https://doi.org/10.1038/sj.onc.1208201

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