Gadd45a regulates β-catenin distribution and maintains cell–cell adhesion/contact

Abstract

Gadd45a, a growth arrest and DNA-damage gene, plays important roles in the control of cell cycle checkpoints, DNA repair and apoptosis. We show here that Gadd45a is involved in the control of cell contact inhibition and cellcell adhesion. Gadd45a can serve as an adapter to enhance the interaction between b-catenin and Caveolin-1, and in turn induces b-catenin translocation to cell membrane for maintaining cell-cell adhesion/contact inhibition. This is coupled with reduction of b-catenin in cytoplasm and nucleus following Gadd45a induction, which is reflected by the downregulation of cyclin D1, one of the b-catenin targeted genes. Additionally, Gadd45a facilitates ultraviolet radiation-induced degradation of cytoplasmic and nuclear b-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, which might contribute to the role of Gadd45a in inhibiting tumorigenesis.

Gadd45a inhibits cell migration and invasion by altering the global RNA expression

“…18 Our previous work has found that Gadd45a could induce β-catenin translocation to cell membrane for maintaining cell-cell adhesion/contact inhibition, which might contribute to its tumor suppressive function. 17 However, the detailed mechanism is still poorly understood.…”

“…16 Meanwhile, our previous study has revealed that Gadd45a maintained cell-cell adhesion and cell contact inhibition by regulating β-catenin subcellular distribution. 17 However, little is known about how Gadd45a participates in the suppression of cell malignancy.…”

Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

“…Cell-cell adhesion (CCA) assay was performed as described (Ji et al, 2007). Melanocytes were plated in 12-well plates.…”

“…Cells were lysed in PNP buffer (phosphate-buffered saline, 0.5% Nonidet P-40, 0.5 mmol/l sodium orthovanadate, 1 mmol/l sodium fluorine, 0.3 mmol/l disodium b-glycerophosphate and protease inhibitors (Sigma-Aldrich)), and the cellular proteins of fraction were extracted as described (Ji et al, 2007). The protein concentration was determined by DC assay (Bio-Rad, Hercules, CA, USA).…”

Exploit and Repurpose? Targeting the Complex Rules of GADD

“…The molecular kinetics of GADD proteins specific to the type of cancer and type of genotoxic stress in relation to the timing of cell cycle checkpoint genes needs further investigation. Others have reported that GADD45α protein physically interacts with β-catenin and Caveolin-1 in HeLa and MEF cells and impacts the localization of β-catenin to the cell membrane rather than the nucleus [8]. Again, in this scenario, GADD45α protein has a driving role in transcriptional inhibition.…”