Transcriptional repression of IKK? by p53 in arsenite-induced GADD45? accumulation and apoptosis.

ABSTRACT: Our previous studies revealed that GADD45? 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 GADD45? accumulation and cell apoptosis. In the present study, we found that one of the catalytic subunits of I?B kinase (IKK), IKK?, exerted a novel IKK?- and NF-?B-independent function in stabilizing MDM2 and therefore contributed to ubiquitination-dependent degradation of GADD45? 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? transcription, reduced MDM2 stability, and ultimately removed the inhibitory effect of MDM2 on GADD45? induction. In addition, DAPK1 functioned as an upstream protein kinase triggering p53/Ets-1-dependent IKK? and MDM2 reduction and GADD45? accumulation, thus promoting apoptosis in HepG2 cells. Subsequent studies further revealed that the activation of the DAPK1/p53/Ets-1/IKK?/MDM2/GADD45? 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? in negatively regulating GADD45? protein stability and the contribution of p53-dependent IKK? reduction to mediating cancer cell apoptosis.

SUBMITTER: Hu Y 

PROVIDER: S-EPMC6355650 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature