BCR-ABL regulates phosphatidylinositol 3-kinase-p110gamma transcription and activation and is required for proliferation and drug resistance.
The BCR-ABL oncogene is the hallmark of chronic myeloid leukemia, a clonal hematopoietic stem cell disorder. BCR-ABL displays constitutive tyrosine kinase activity, required for its transformation ability. Although the molecular mechanisms behind this malignancy are not fully understood, a role for phosphatidylinositol (PI) 3-kinase has been repeatedly described. Here we report the specific up-regulation of the class I(B) catalytic subunit of PI 3-kinase (p110gamma) in response to BCR-ABL expression. We demonstrate that this upregulation is due to increased transcription and is dependent on both PI 3-kinase and MEK activity. We performed in vitro kinase activity assays and show that BCR-ABL also leads to increased p110gamma activity and that this activation requires both G protein-coupled receptor and Ras signaling. In addition, by transfection of cells with dominant negative p110gamma, we determined that this specific PI 3-kinase isoform is involved in both proliferation and the apoptosis resistance associated with chronic myeloid leukemia. The data presented here define for the first time the ability of BCR-ABL to alter the expression levels of PI 3-kinase isoforms and also demonstrate a previously unreported link between BCR-ABL and p110gamma.
Hickey
Fionnuala B
FB
Department of Biochemistry, Biosciences Institute, University College Cork, Cork, Ireland.
Cotter
Thomas G
TG
D017209:Apoptosis; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D004351:Drug Resistance; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
D043562:Receptors, G-Protein-Coupled; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins