Bcr-Abl-mediated redox regulation of the PI3K/AKT pathway.
Bcr-Abl causes chronic myelogenous leukemia, a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells. In this study, inducible expression of Bcr-Abl in TonB.210 cells is associated with increased production of intracellular reactive oxygen species (ROS), which is thought to play a role in survival signaling when generated at specific levels. Elevated ROS in Bcr-Abl-expressing cells were found to activate PI3k/Akt pathway members such as Akt and GSK3beta as well as downstream targets beta-catenin and Mcl-1. The activation of these proteins was inhibited by the flavoprotein inhibitor diphenyleneiodonium, which is commonly used to inhibit NADPH oxidase (Nox). This indicated that increased ROS might be related to increased activity of one member of the Nox family. Knock-down experiments using siRNA suggest that Nox-4 is the main source of increased ROS following Bcr-Abl expression. We showed that Bcr-Abl-induced ROS could also increase survival pathway signaling through redox inhibition of PP1alpha, a serine threonine phosphatase that negatively regulates the PI3k/Akt pathway. Overall our results demonstrate that Bcr-Abl expression increases Nox-4-generated ROS, which in turn increases survival signaling through PI3k/Akt pathway by inhibition of PP1alpha, thus contributing to the high level of resistance to apoptosis seen in these Bcr-Abl-expressing cells.
Naughton
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R
Tumour Biology Laboratory, Biochemistry Department, Bioscience Research Institute, University College, Cork, Ireland.
Quiney
C
C
Turner
S D
SD
Cotter
T G
TG
D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000503:physiopathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009861:Onium Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D051176:beta Catenin; C007517:diphenyleneiodonium; D006861:Hydrogen Peroxide; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; C494918:AKT1 protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D054645:Protein Phosphatase 1