Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin.
Caspase-1, a cysteine protease is primarily involved in proteolytic activation of proinflammatory cytokines such as interleukin-1beta. It is also involved in some forms of apoptosis. Here we have analyzed the role of p73, a homolog of tumor suppressor p53, in regulating human caspase-1 gene transcription. The caspase-1 promoter was strongly activated by p73alpha and p73beta primarily through a p53/p73 responsive site. Overexpression of p73 by transient transfection increased the caspase-1 mRNA level. Treatment of cells with cisplatin (which increases p73 protein level) resulted in increased caspase-1 promoter activity and its mRNA level. Blocking of p73 function by a dominant negative mutant reduced basal as well as cisplatin-induced caspase-1 promoter activity. Mutation of the p73 responsive site abolished cisplatin-induced activation of the promoter. Interferon-gamma induced caspase-1 promoter activity and this was reduced by p73-directed small hairpin RNA and also by a dominant negative mutant of p73. Abrogation of the p73 responsive site partially inhibited interferon-gamma-induced activation of the caspase-1 promoter. Treatment of HeLa cells with interferon-gamma resulted in an increase in p73 protein as well as its activity. Mutation of the IRF-1 binding site abolished interferon-gamma-induced caspase-1 promoter activity but p73-induced activation was only marginally reduced. IRF-1 cooperated with p73 and cisplatin cooperated with interferon-gamma in the activation of the caspase-1 promoter. Our results show that p73 is a regulator of caspase-1 gene transcription, and is required for optimal activation of the caspase-1 promoter by interferon-gamma.
Jain
Nishant
N
Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.
Gupta
Sanjeev
S
Sudhakar
Ch
Ch
Radha
Vegesna
V
Swarup
Ghanshyam
G
D000970:Antineoplastic Agents / Q000494:pharmacology*; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050436:Regulatory Elements, Transcriptional; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation; D014162:Transfection; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D007371:Interferon-gamma; D020170:Caspase 1; D002945:Cisplatin