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Title: Role of calpain and cofilin in apoptosis regulation
Keywords: calpain; caspase; mitochondria; cofilin; translocation; phosphorylation
Issue Date: 4-Jun-2004
Citation: CHUA BOON TIN (2004-06-04). Role of calpain and cofilin in apoptosis regulation. ScholarBank@NUS Repository.
Abstract: Apoptosis is a form of programmed cell death. Here, we investigated caspase and mitochondria regulation during the process. Caspases is a family of cysteine proteases involved in cytokine activation and execution of apoptosis. In this report, we demonstrated the cleavage of caspase-7, -8 and a??9 by calcium-activated calpains. Calpain cleaved caspase-9 at two sites. Cleaved caspase-9 is unable to activate caspase-3 nor respond to dATP/cytochrome c activation, resulting in the protection of cells from H7-induced caspase-dependent apoptosis. Our results suggest that calpains act as negative regulators of apoptosis by effectively inactivating caspases.Next, we demonstrated that cofilin, the actin depolymerising protein, translocates to mitochondria at early stages of apoptosis. Translocation was achieved through the exposure of an N-terminal mitochondrial-targeting signal, dephosphorylation of serine 3 and C-terminal domain. Silencing cofilin or overexpression of cofilin S3D mutant that mimics the phosphorylated form, suppressed apoptosis. The apoptosis-inducing ability of cofilin, but not its mitochondrial localisation, was dependent on the functional actin-binding domain. Our data demonstrate that cofilin plays a critical role in the initiation of apoptosis via its association with mitochondria, resulting in cytochrome c release and caspase activation.
Appears in Collections:Ph.D Theses (Open)

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