Caspase-9 can antagonize p53-induced apoptosis by generating a p76(Rb) truncated form of Rb.

The tumor suppressor Rb (retinoblastoma protein) is known to regulate p53-dependent apoptosis, but the mechanisms involved are unclear. In a rat fibroblast model, we previously observed that caspase inhibition potentiates p53-dependent apoptosis and prevents the Rb cleavage associated with p53 activation. These results suggested that a caspase(s) can antagonize p53-mediated ...
apoptosis via the production of a protective Rb truncated form. Here, we identify caspase-9 as the caspase that interferes, upstream of the mitochondrion, with p53-induced apoptosis in both immortalized and primary fibroblasts. This caspase can be detected as a p38 processed form in living cells, in the absence of apoptosome formation and apoptotic signal. We also provide evidence that the involvement of caspase-9 in a pre-mitochondrial protective pathway results from the previously undescribed cleavage of Rb, at a LExD site, into a p76(Rb) form, which antagonizes p53-induced apoptosis. These results establish that a truncated form of Rb can display an antiapoptotic activity, rather than just being a by-product of Rb degradation.
Mesh Terms:
Animals, Antineoplastic Agents, Phytogenic, Apoptosis, Blotting, Western, Caspase 9, Caspases, Cell Line, Cell Survival, Cloning, Molecular, Enzyme Inhibitors, Etoposide, Fibroblasts, Humans, Kinetics, Models, Genetic, Necrosis, Plasmids, Protein Structure, Tertiary, Rats, Retinoblastoma Protein, Staurosporine, Temperature, Tumor Suppressor Protein p53
Oncogene
Date: May. 05, 2005
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