Format

Send to

Choose Destination
J Biol Chem. 2005 Nov 4;280(44):36664-73. Epub 2005 Aug 31.

Role of p73 in regulating human caspase-1 gene transcription induced by interferon-{gamma} and cisplatin.

Author information

1
Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500007, India.

Abstract

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.

PMID:
16135520
DOI:
10.1074/jbc.M413261200
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center