title: Full activation of PKB/Akt in response to insulin or ionizing radiation is mediated through ATM.
abstract: The gene mutated in ataxia telangiectasia, ATM, has been implicated in several cell functions such as cell cycle control and response to DNA damage and insulin. PKB/Akt has also been implicated in the cellular response to insulin, gamma-radiation, and cell cycle control. Interestingly, lack of PKB/Akt function in vivo is able to mimic some phenotypic abnormalities associated with ataxia telangiectasia (AT). Here we show that ATM is a major determinant of full PKB/Akt activation in response to insulin or gamma-radiation. This effect is mediated through the phosphatidylinositol 3-kinase domain of ATM that specifically affects Akt serine 473 phosphorylation. This conclusion was inferred from the results obtained in transient transfection assays using exogenous PKB/Akt and ATM in Cos cells. Moreover, the use of ATM inhibitors or small interfering RNA confirmed our observation. Further supporting these results, we also observed that biological responses tightly regulated by Akt, such as transcription factor of the forkhead family activity after insulin treatment or gamma-radiation response, were altered in cell lines derived from AT patients and knockout mice for ATM in which phosphorylation in serine 473 was almost abolished. This study proposes new clues in the search of the unknown PDK2 and new explanations for the radiosensitivity or insulin intolerance described more than 30 years ago in AT patients.
authors.affiliation: CRIB/Facultad de Medicina, Universidad de Castilla la Mancha, 02071 Albacete, Spain.
authors.forename: Juan Guinea
authors.initials: JG
authors.lastname: Viniegra
authors.forename: Natalia
authors.initials: N
authors.lastname: Martínez
authors.forename: Pegah
authors.initials: P
authors.lastname: Modirassari
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández Losa
authors.forename: Carlos
authors.initials: C
authors.lastname: Parada Cobo
authors.forename: Víctor Javier
authors.initials: VJ
authors.lastname: Sánchez-Arévalo Lobo
authors.forename: Clara Isabel
authors.initials: CI
authors.lastname: Aceves Luquero
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez-Vallina
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramón y Cajal
authors.forename: José María
authors.initials: JM
authors.lastname: Rojas
authors.forename: Ricardo
authors.initials: R
authors.lastname: Sánchez-Prieto
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000378:metabolism; D005720:Gamma Rays; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D012694:Serine / Q000737:chemistry; D013997:Time Factors; D014162:Transfection; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D012694:Serine; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; C576324:ATM protein, human; C576325:Atm protein, mouse