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J. Biol. Chem., Vol. 276, Issue 14, 10585-10588, April 6, 2001

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ACCELERATED PUBLICATION
Direct Transcriptional Activation of Human Caspase-1 by Tumor Suppressor p53^*

Sanjeev Gupta, Vegesna Radha, Yusuke Furukawa^§, and Ghanshyam Swarup^¶

From the  Centre for Cellular and Molecular Biology, Hyderabad 500 007, India and ^§ Division of Molecular Hemopoiesis, Centre for Molecular Medicine and Department of Hematology, Jichi Medical School, Tochigi 329-0498, Japan

The tumor suppressor protein p53 is a sequence-specific DNA-binding protein, and its biological responses are very often mediated by transcriptional activation of various target genes. Here we show that caspase-1 (interleukin-1 converting enzyme), which plays a role in the production of proinflammatory cytokines and in apoptosis, is a transcriptional target of p53. Caspase-1 mRNA levels increased upon overexpression of p53 by transfection in MCF-7 cells. Human caspase-1 promoter showed a sequence homologous to the consensus p53-binding site. This sequence bound to p53 in gel shift assays. A caspase-1 promoter-reporter construct was activated 6-8-fold by cotransfection with normal p53 but not by mutant p53 (His²⁷³) in HeLa, as well as MCF-7, cells. Mutation of the p53-binding site in caspase-1 promoter abolished transactivation by p53. Treatment of p53-positive MCF-7 cells with the DNA-damaging drug, doxorubicin, which increases p53 levels, enhanced caspase-1 promoter activity 4-5-fold, but similar treatment of MCF-7-mp53 (a clone of MCF-7 cells expressing mutant p53) and p53-negative HeLa cells with doxorubicin did not increase caspase-1 promoter activity. Doxorubicin treatment increased caspase-1 mRNA levels in MCF-7 cells but not in MCF-7-mp53 or HeLa cells. These results show that endogenous p53 can regulate caspase-1 gene expression.

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