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Involvement of caspase 1 and its activator Ipaf upstream of mitochondrial events in apoptosis
Author(s) -
Thalappilly Subhash,
Sadasivam Subhashini,
Radha Vegesna,
Swarup Ghanshyam
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2006.05293.x
Subject(s) - apoptosis , activator (genetics) , cytochrome c , caspase 3 , caspase , microbiology and biotechnology , chemistry , biology , biochemistry , programmed cell death , gene
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‐dependent 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 apoptosis and that caspase 1, when activated by Ipaf, causes release of mitochondrial proteins (cytochrome c and Omi) through Bax activation, thereby functioning as an initiator caspase.