PI3K/AKT and Mdm2 activation are associated with inhibitory effect of cAMP increasing agents on DNA damage-induced cell death in human pre-B NALM-6 cells.

ABSTRACT

DNA damage response (DDR) consists of both proapoptotic and prosurvival signaling branches. Superiority of each signaling branch determines the outcome of DNA damage death or allowing the repair. The present authors have previously shown that an increased intracellular level of cAMP disrupts p53-mediated apoptosis in human pre-B NALM-6 cells and inhibition of NF-κB prevents prosurvival effect of cAMP during DNA damage. AKT/PKB (protein kinase B) is a general mediator of survival signaling. AKT signaling inhibits p53-mediated transcription and apoptosis. The results of present study showed that cAMP disrupted DNA damage/p53-mediated apoptosis through AKT and subsequent NF-κB activation. These results suggested that AKT may be found as part of a complex with scaffolding proteins, beta-arrestins and PDE4D. cAMP disarticulated the complex through binding to PDE4D compartment. It seems that release of AKT protein potentiated DDR activated pro-survival AKT in NALM-6 cells. Taken together, the present data indicated that regulation of AKT signaling may determine the fate of cells exposed to genotoxic stress.