Role of p73 in regulating human caspase-1 gene transcription induced by interferon-γ and cisplatin

Caspase-1, a cysteine protease is primarily involved in proteolytic activation of proinflammatory cytokines such as interleukin-1β. 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 p73α and p73β 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-γ 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-γ-induced activation of the caspase-1 promoter. Treatment of HeLa cells with interferon-γ resulted in an increase in p73 protein as well as its activity. Mutation of the IRF-1 binding site abolished interferon-γ-induced caspase-1 promoter activity but p73-induced activation was only marginally reduced. IRF-1 cooperated with p73 and cisplatin cooperated with interferon-γ 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-γ.