Ribosomal protein S7 regulates arsenite-induced GADD45α expression by attenuating MDM2-mediated GADD45α ubiquitination and degradation

The stress-responding protein, GADD45 alpha, plays important roles in cell cycle checkpoint, DNA repair and apoptosis. In our recent study, we demonstrate that GADD45 alpha undergoes a dynamic ubiquitination and degradation in vivo, which process can be blocked by the cytotoxic reagent, arsenite, resulting in GADD45 alpha accumulation to activate JNKs cell death pathway, thereby revealing a novel mechanism for the cellular GADD45 alpha functional regulation. But the factors involved in GADD45 alpha stability modulations are unidentified. Here, we demonstrated that MDM2 was an E3 ubiquitin ligase for GADD45 alpha. One of MDM2-binding partner, ribosomal protein S7, interacted with and stabilized GADD45 alpha through preventing the ubiquitination and degradation of GADD45 alpha mediated by MDM2. This novel function of S7 is unrelated to p53 but seems to depend on S7/MDM2 interaction, for the S7 mutant lacking MDM2-binding ability lost its function to stabilize GADD45 alpha. Further investigations indicated that arsenite treatment enhanced S7-MDM2 interaction, resulting in attenuation of MDM2-dependent GADD45 alpha ubiquitination and degradation, thereby leading to GADD45 alpha-dependent cell death pathway activation. Silencing S7 expression suppressed GADD45 alpha-dependent cytotoxicity induced by arsenite. Our findings thus identify a novel function of S7 in control of GADD45 alpha stabilization under both basal and stress conditions and its significance in mediating arsenite-induced cellular stress.