Gadd45α Contributes To Tumor Suppression Through Inducing β-catenin Accumulation In Cell Membrane And Increasing The Stability Of Smad4 Protein

Gadd45a has been implicated in the control of cell cycle progression, probably through its roles in the cell cycle checkpoint, DNA repair and apoptosis. Disruption of endogenous Gadd45a results in tumorigenesis and development of malignancy although the mechanism(s) remains to be further elucidated.In the first part of dissertation, we show here that Gadd45a is involved in the process of cell contact inhibition and cell-cell adhesion. Gadd45a can serve as an adapter to enhance the interaction between β-catenin and Caveolin-1, and in turn induce β-catenin translocation to cell membrane for maintaining cell-cell adhesion/contact inhibition. This is coupled with reduction of P-catenin in cytoplasm and nucleus following Gadd45a induction, which is reflected by the down-regulation of Cyclin D1, one of the β-catenin targeted genes. Additionally, Gadd45a facilitates UV radiation-induced degradation of β-catenin in a p53-dependent manner via activation of p38 kinase. These findings define a novel link that connects Gadd45a to cell-cell adhesion and cell contact inhibition.In the second part of dissertation, we show here that Gadd45a is involved in regulating TGF-β/Smad pathway. Increased Gadd45a interacts with β-Trcp1, an F-box protein of SCF E3 ligase. Moreover, this interaction is enhanced with Gadd45a induction and consequently suppresses the degradation of Smad4 and Smad3 by SCF^β-Trcp1. The increasing teady-level of Smads by Gadd45a contributes to the restoration of the TGF-β-induced growth inhibition. In addition, Gadd45a expression also induces the decreasing of S phase, up-regulation of p21 and down-regulation of VEGF transcripts through Smad4. All these findings support the role of Gadd45a in...