Differential regulation of apoptosis in AK-5 tumor cells by the proto-oncogene Bcl-2: presence of Bcl-2 dependent and independent pathways.
The anti-apoptotic protein Bcl-2 functions as a crucial negative regulator of apoptosis. Bcl-2 has been shown to prevent the efflux of apoptogenic factors from mitochondria to cytosol, thus inhibiting cell death. Here, we show the susceptibility of a spontaneously regressing, rat histiocytic tumor cell line, AK-5, to the apoptotic effects of diverse stimuli and the ability of Bcl-2 overexpression to block cell death. Bcl-2 overexpression selectively inhibits apoptosis induced by ceramide and serum factor from AK-5 tumor regressing animals but not actinomycin D and curcumin, whereas the pancaspase inhibitor z-Val-Ala-Asp fluoromethylketone completely blocks apoptosis, irrespective of the inducer used. The ability of Bcl-2 overexpression to block cell death does not depend on its ability to prevent cytochrome c release but correlates with its ability to prevent the dissipation of mitochondrial transmembrane potential. The results demonstrate that there are inducer dependent redundant activation pathways in a single cell, which may either be Bcl-2 dependent or independent.
Anjum
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Centre for Cellular and Molecular Biology, Uppal Road, 500 007, Hyderabad, India.
Khar
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D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002518:Ceramides / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003574:Cytochrome c Group / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005434:Flow Cytometry; D015870:Gene Expression; D019254:Genes, bcl-2 / Q000235:genetics*; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D013935:Thymic Factor, Circulating / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D002518:Ceramides; D015853:Cysteine Proteinase Inhibitors; D003574:Cytochrome c Group; D019253:Proto-Oncogene Proteins c-bcl-2; D003609:Dactinomycin; D013935:Thymic Factor, Circulating; D020169:Caspases; D003474:Curcumin