The Proto-Oncoprotein c-Cbl Protects Cells against Oxidative Stress by Down-Regulating Apoptosis and is Highly Expressed in Several Cancers

The proto-oncoprotein c-Cbl controls several down-regulation signals leading to degradation of tyrosine-kinase receptors (TKR) [1-3] or endocytic trafficking [1,4,5]. It interacts with numerous signalling proteins through their Src homology-2 or -3 (SH2 or SH3) domains [6,7]. Several groups, including ours, have reported an association between down-regulation of apoptosis and c-Cbl. First, oncogenic forms of c-Cbl are anti-apoptotic [8]. The pro-apoptotic Bim EL BH3only protein has been shown to be down-regulated by c-Cbl in primary culture of osteoclastes [9]. We found a similar, though probably indirect, regulation of BimEL through c-Cbl in mouse testicular germ cells and extended these findings to the pro-apoptotic factor Smac/ DIALO [10], indicating that c-Cbl likely exerts an anti-apoptotic effect. Langdon et al. reported that a c-Cbl RING finger mutant leads to thymocyte apoptosis and to an unexpected Akt activation, as well as an increase expression of Bim EL [11,12]. Sproul et al., using PC12 cells and primary cultures of neurons [13], reinforced the anti-apoptotic effect of c-Cbl, reporting that c-Cbl inhibits the ability of mixedlineage kinase (MLK), from the mitogen-activated protein (MAP) kinase family, to activate c-Jun N-terminal kinase (JNK). Finally, it has been reported that c-Cbl regulates the degradation of the pro-apoptotic TRAIL receptors [14,15] and that the TRAIL/MEKK4/HSP27/Akt survival network is modulated by the Src/CIN85-c-Cbl complex [16].