The Role Of Chip In Bone Modeling And Hepatocarcinogenesis

Carboxyl terminus of Hsc70-interacting protein (CHIP or STUB1) is an E3ligaseand regulates the stability of several proteins which are involved in tumor growth andmetastasis, the nervous and the immunesystem regulation. However, the role of CHIP inbone growth and bone remodeling has not been reported. The objective of this study isto investigate the role and mechanism of CHIP in regulation of bone remodeling.In this study, we found that deletion of the Chip gene leads to osteopenicphenotype and increased osteoclast formation. We further found that TRAF6, as a novelsubstrate of CHIP, is up-regulated in Chipknockout osteoclasts. TRAF6is critical forRANKL-induced osteoclastogenesis. CHIP interacts with TRAF6to promote TRAF6ubiquitination and proteasome degradation. In Chipknockout osteoclasts, thephosphorylation of IKKα/β and IκBαand the nuclear translocation of p65wereincreased. Furthermore, NF-κB activity was enhanced. Therefore, CHIP inhibits NF-κBsignaling via promoting TRAF6degradation and plays an important role inosteoclastogenesis and bone resorption. Moreover, we found that the bone formationrate andthe osteoblast activity were decreased in Chip knockout mice. These resultsdemonstrate that CHIP might be a positive regulator of osteoblastogenesis and boneformation. Therefore, our study suggests that CHIP may be a novel therapeutic targetfor the treatment of bone loss associated diseases.TRAF6mediated NF-κB signaling pathway also plays a critical role in tumorsgrowth and angiogenesis. In this study, we found that CHIP interacts with TRAF6topromote its degradation. CHIP attenuates IL-1β-induced the phosphorylation of IKKα/βand IκBα and inhibits p65trans-localization into nucleus, which led to repression of theTRAF6-mediated NF-κB transcription in HepG2cells. Over-expression of CHIP inHepG2cells blocks expression of NF-κB targeting genes, including IL-6, IL-8andCOX2. We further observed that CHIP inhibits NF-κB activated proliferation andcolony formation in HepG2cells. We conclude that CHIP inhibits NF-κ signaling viapromoting TRAF6degradation and may act as a tumor suppressor for hepatoma tumor.