The Molecular Mechanism Of NRAGE In Suppression Cell Proliferation, Adhesion And Migration

NRAGE (neurotrophin receptor-interacting MAGE homolog) is a recently identified molecule belonging to the MAGE (melanoma antigen) protein family. The expression of most MAGE proteins is restricted to cancer cells; however, NRAGE is expressed in many normal tissues in early development and adult stage. Recent experiments revealed that NRAGE is downregulated in some types of cancers, which implicated that NRAGE is concerned with carcinogenesis. Molecular studies showed that NRAGE is a multifunctional protein, which interacts with a number of proteins by its WQXPXX repeats domain and MAGE homologue domain (MHD) to play different functions. NRAGE interacts with the nerve growth factor receptor p75NTR, XIAP (X-linked inhibitor of apoptosis), UNC5H1 and PrPc for regulating cell proliferation and apoptosis; interacts with dlx5 for regulating its transcriptional activity; interacts with necdin and Msx2 to promote myogenic differentiation of C2C12 cells; and also interacts with Ror2 to determine the subcellular distribution of itself. However, the precise function of NRAGE involved in cell signal transduction is elusive.Now, we investigate the funtions of NRAGE in cell apoptosis , adhesion and migration systematically. Our results show as follow:1. NRAGE can activate p53 pathway by directly interaction with N-terminal of p53, which is also required for Mdm2 binding. And then NRAGE inhibits the p53 degradation of p53 induced by Mdm2, which leads to cell cycle arrest at G0/G1 and G2/M stages and cell apoptosis under UV stress.2. NRAGE can disrupt the E-cadherin/β-catenin complex, translocates β-catenin from cell membrane into cell cytoplasm and cell nuclei, then inhibits E-cadherin mediated cell-cell adhesion.3. NRAGE suppresses Wnt signal pathway markedly. Overexpression of NRAGE can...