tailieunhanh - Báo cáo khoa học: Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis

PTP-S2⁄TC45 is a nuclear protein tyrosine phosphatase that activates p53 and induces caspase 1-dependent apoptosis. We analyzed the role of ICE protease-activating factor (Ipaf), an activator of caspase 1 in p53-depend-ent apoptosis. We also determined the sequence of events that lead to apoptosis upon caspase 1 activation by Ipaf. | iFEBS Journal Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis Subhash Thalappilly Subhashini Sadasivam Vegesna Radha and Ghanshyam Swarup Centre for Cellular and Molecular Biology Hyderabad India Keywords apoptosis caspase 1 Ipaf p53 protein tyrosine phosphatase Correspondence G. Swarup Centre for Cellular and Molecular Biology UppalRoad Hyderabad 500 007 India Fax 91 40 2716 0591 Tel 91 40 2716 022 E-mail gshyam@ Received 2 January 2006 revised 1 March 2006 accepted 25 April 2006 doi PTP-S2 TC45 is a nuclear protein tyrosine phosphatase that activates p53 and induces caspase 1-dependent apoptosis. We analyzed the role of ICE protease-activating factor Ipaf an activator of caspase 1 in p53-depend-ent apoptosis. We also determined the sequence of events that lead to apoptosis upon caspase 1 activation by Ipaf. PTP-S2 expression induced Ipaf mRNA in MCF-7 cells which was dependent on p53. PTP-S2-induced apoptosis was inhibited by a dominant-negative mutant of Ipaf and also by an Ipaf-directed short-hairpin RNA. Doxorubicin-induced apoptosis was potentiated by the expression of caspase 1 but not by a catalytic mutant of caspase 1 and required endogenous Ipaf. Doxorubicin treatment of MCF-7 cells resulted in activation of exogenous caspase 1 which was partly dependent on endogenous Ipaf. An activated form of Ipaf induced caspase 1-dependent apoptosis that was inhibited by Bcl2 and also by a dominant inhibitor of caspase 9 caspase 9s . Caspase 1-dependent apoptosis induced by doxorubicin was also inhibited by Bcl2 and caspase 9s but caspase 1 activation by activated Ipaf was not inhibited by Bcl2. Mitochondrial membrane permeabilization was induced by caspase 1 and activated Ipaf which was inhibited by Bcl2 but not by caspase 9s. Expression of caspase 1 with activated Ipaf resulted in the activation of Bax at mitochondria. Our results suggest that Ipaf is involved in PTP-S2-induced