Ring Refers To The Molecular Mechanism Of Protein The Rlim Enhanced P53 Protein Stability

The p53 tumor suppressor is critical for maintenance of genome stability and protection against malignant transformation. p53 mutations have been documented in more than half of all human tumors. defects in other components of the p53 pathway, such as the ARF tumor suppressor, are observed in tumor cells that retain wild-type p53. Thus, inactivation of the p53 pathway way appears to be common event in human cacner.The cellular functions of p53 are rapidly activated in response to various stresses, to mediate cell cycle arrest and apoptosis. p53 is tightly regulated by multiple signal pathways and mechanisms, Its turnover is regulated by MDM2, which binds p53 and functions as an ubiquitin E3 ligase to promote p53 ubiquitination and degradation by the proteasomes.In an effort to identify HCC relevant genes, we used differential display to identify a gene-RLIM (for RING finger LIM domain-binding protein) which is significantly down regulated in HCC tissues sample, The downregulation was confirmed with semi-immunohistochemistry,RT-PCR,and Western Blot methods. RLIM is E3 ubiquitin ligase which contains an RING finger domain. Precious report has identified RLIM is able to target LIM-HD cofactors, such as CLIM,LMO2/LMO4 for degradation through the 26S proteasome pathway. We demonstrate that RLIM can specifically activate p53 pathway in Luc-reporter system, enhance p53 stability, promote p53-dependent apoptosis and cell growth arrest, We demonstrate RLIM could specifically associates with the p53 and is able to promote its ubiquitination in vitro and in vivo .but this kind of ubiquitination is really weak in vivo, and could explain RLIM as a positive regulator. In vitro and in vivo experiments revealed that RLIM binds to MDM2, cause MDM2 instability. RLIM could ubiquitnate MDM2 independent of MDM2 self-ubiquitination. RLIM-mediated ubiquitination of MDM2 occurs at N terminal sites distinct from those self- ubiquitination sites. Furthermore, RLIM could positively regulate p53 in an ubiquitin ligase-independent way. Depletion of endogenous RLIM by RNAi decreased the rate of UV-induced apoptosis in U2OS cells expressing functional p53. It could phosphorylated by DNA damage-related kinase-Chk1, It suggest its role towards p53 may controlled by upstream signaling pathway, Taken together, these findings identify a p53 positive regulator-RLIM,and a novel mdm2 stability regulation pathway. We also discuss its possible roles in HCC tumorigenesis.