Our previous studies revealed that GADD45 alpha is a liable protein, which undergoes MDM2-dependent constitutive ubiquitination and degradation in resting HepG2 hepatoma cells. Arsenite exposure induces ribosomal stress responses mediated by the ribosomal protein S7, which can block MDM2 activity and result in GADD45a accumulation and cell apoptosis. In the present study, we found that one of the catalytic subunits of I.B kinase (IKK), IKK beta, exerted a novel IKK alpha -and NF-kappa B-independent function in stabilizing MDM2 and therefore contributed to ubiquitination-dependent degradation of GADD45 alpha in resting HepG2 cells. Arsenite stimulation induced transactivation of p53, which formed a complex with its downstream target, Ets-1, and then synergistically repressed IKK beta transcription, reduced MDM2 stability, and ultimately removed the inhibitory effect of MDM2 on GADD45 alpha induction. In addition, DAPK1 functioned as an upstream protein kinase triggering p53/Ets-1-dependent IKK beta and MDM2 reduction and GADD45 alpha accumulation, thus promoting apoptosis in HepG2 cells. Subsequent studies further revealed that the activation of the DAPK1/p53/Ets-1/IKK beta/MDM2/GADD45 alpha cascade was a common signaling event in mediating apoptosis of diverse cancer cells induced by arsenite and other tumor therapeutic agents. Therefore, we conclude that data in the current study have revealed a novel role for IKK beta in negatively regulating GADD45 alpha protein stability and the contribution of p53-dependent IKK beta reduction to mediating cancer cell apoptosis.