title: Caspase-1 activator Ipaf is a p53-inducible gene involved in apoptosis.
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 His(273) 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.
authors.affiliation: Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
authors.forename: Subhashini
authors.initials: S
authors.lastname: Sadasivam
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
authors.forename: Vegesna
authors.initials: V
authors.lastname: Radha
authors.forename: Kiran
authors.initials: K
authors.lastname: Batta
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
authors.forename: Ghanshyam
authors.initials: G
authors.lastname: Swarup
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D004317:Doxorubicin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002135:Calcium-Binding Proteins; C435692:NLRC4 protein, human; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D020170:Caspase 1