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Abstract
Apoptosis Inducing Factor is a mitochondrial protein which upon translocation to nucleus
causes large scale DNA fragmentation. The stimulus for the cytosolic release and nuclear
translocation for this protein still remains to be understood. The role of calpains,
cathepsin-b, Poly ADP (ribose) Polymerase and granzyme-b in the nuclear translocation
of AIF has been investigated in the pathology of cerebral ischemia. Calpains, cathepsin-b
and PARP-1 which were mostly confined to cytosol, lysosomes and nucleus respectively
were found to be elevated in the mitochondrial fraction interacting with AIF in the
western blot analysis and double immunofluorescence analysis. Western blot and immunohistochemical
analysis revealed elevated levels of granzyme-b secreted by cytotoxic T lymphocytes
and natural killer cells in the infarct of ischemic mouse brain. Co-immunoprecipitation
revealed and western blot analysis the interaction and break down of Heat Shock Protein-70
an endogenous inhibitor of AIF into signature fragments by granzyme-b facilitating
the nuclear translocation of AIF. Break down of HSP-70 correlated with the nuclear
translocation of AIF observed in western and immunohistochemical analysis. These results
indicate that multiple proteases were involved in the nuclear translocation of AIF
during the pathology of cerebral ischemia.