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.
Lemaire
Christophe
C
Laboratoire de Génétique et Biologie Cellulaire, CNRS FRE 2445, Université de Versailles/St Quentin-en-Yvelines, 45 avenue des Etats-Unis, 78035 Versailles cedex, France.
Godefroy
Nelly
N
Costina-Parvu
Ioana
I
Rincheval
Vincent
V
Renaud
Flore
F
Trotot
Pascale
P
Bouleau
Sylvina
S
Mignotte
Bernard
B
Vayssière
Jean-Luc
JL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D003001:Cloning, Molecular; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008957:Models, Genetic; D009336:Necrosis; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D005047:Etoposide; C506433:CASP9 protein, human; C506435:Casp9 protein, rat; D053453:Caspase 9; D020169:Caspases; D019311:Staurosporine