[Implication of the ubiquitin ligase c-Cbl in bone formation and tumorigenesis]

Cbl ubiquitin ligases are important molecules that control the process of ubiquitination and degradation of proteins by the proteasome. Because this process regulates several intracellular mechanisms, alterations in Cbl activity lead to several pathologies including cancer. In bone, the c-Cbl ubiquitin ligase is known to control osteoclast activity. Our studies indicate that c-Cbl also regulates osteoblast proliferation, differentiation and survival. We recently showed that inhibition of c-Cbl activity using a c-Cbl mutant leads to promote osteoblast differentiation in mesenchymal stromal cells as a consequence of increased receptor tyrosine kinase expression. Conversely, we found that overexpression of c-Cbl leads to inhibit osteosarcoma cell proliferation and tumorigenesis through downregulation of these receptors. Thus, the use of pharmacological agents capable of modulating c-Cbl activity may be of therapeutic interest for promoting bone formation in normal bone, or to reduce tumorigenesis in primary bone cancer.