title: 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.
authors.affiliation: Faculty of Nutrition and Diet Therapy, Department of Cellular and Molecular Nutrition, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Arman
authors.initials: A
authors.lastname: Ghorbani
authors.affiliation: Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Jeddi-Tehrani
authors.affiliation: National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Atoosa
authors.initials: A
authors.lastname: Saidpour
authors.affiliation: Department of Hematology, Cellular and Molecular Research Center, Faculty of Allied Medicine, Iran University of Medical Sciences, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Safa
authors.affiliation: Monoclonal Antibody Research Center, Avicenna Research Institute, ACECR, Tehran, Iran.
authors.forename: Ahmad Ali
authors.initials: AA
authors.lastname: Bayat
authors.affiliation: National Nutrition and Food Technology Research Institute, Faculty of Nutrition Science and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Electronic address: hamid_zand@sbmu.ac.ir.
authors.forename: Hamid
authors.initials: H
authors.lastname: Zand
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects*; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000077191:Wortmannin; D000071557:beta-Arrestins
chemical_list: D000730:Androstadienes; D000906:Antibodies; D019390:Arrestins; D002867:Chromones; D007546:Isoquinolines; D009025:Morpholines; D016328:NF-kappa B; D013449:Sulfonamides; D013873:Thionucleotides; D016159:Tumor Suppressor Protein p53; D000071557:beta-Arrestins; D005576:Colforsin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000077191:Wortmannin
keywords: AKT (PKB); Cyclic adenosine monophosphate (cAMP); DNA damage response (DDR); Mdm2; NF-κB; p53