Abstract
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 p76Rb 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.
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Acknowledgements
This work was supported by the University of Versailles/Saint Quentin, the Association pour la Recherche contre le Cancer (#4480) and the Ligue Nationale Contre le Cancer. CL was a fellow from the Ligue Nationale Contre le Cancer. NG is supported by a scholarship from the Ministère de l'Education Nationale, de l' Enseignement Supérieur et de la Recherche (MENESR). We thank Dr Laurent Theodore (University of Versailles, Versailles, France) and Dr Anne-Marie Pret (University Pierre et Marie Curie, Paris, France) for critical reading of the manuscript. The dominant negative caspase mutants were a kind gift from Dr Patrick Mehlen (Molecular and Cellular Genetic Center, Villeurbane, France).
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Lemaire, C., Godefroy, N., Costina-Parvu, I. et al. Caspase-9 can antagonize p53-induced apoptosis by generating a p76Rb truncated form of Rb. Oncogene 24, 3297–3308 (2005). https://doi.org/10.1038/sj.onc.1208493
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DOI: https://doi.org/10.1038/sj.onc.1208493
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