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 Publisher Pubmed



Ghorbani A³ ; Jedditehrani M² ; Saidpour A¹ ; Safa M⁴ ; Bayat AA² ; Zand H¹
Source: Archives of Biochemistry and Biophysics Published:2015

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. © 2014 Elsevier Inc. All rights reserved.