Peer-Reviewed Journal Details
Mandatory Fields
Hickey, FB,Cotter, TG;
2006
February
The Journal of Biological Chemistry
BCR-ABL regulates phosphatidylinositol 3-kinase-p110 gamma transcription and activation and is required for proliferation and drug resistance
Validated
()
Optional Fields
PROTEIN-KINASE-C G-BETA-GAMMA POSITIVE PHILADELPHIA-CHROMOSOME CHRONIC MYELOGENOUS LEUKEMIA MESSENGER-RNA STABILITY PHOSPHOINOSITIDE 3-KINASE CELL-LINE CONSTITUTIVE ACTIVATION LYSOPHOSPHATIDIC ACID HEMATOPOIETIC-CELLS
281
2441
2450
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 PI3-kinase (p110 gamma) in response to BCR-ABL expression. We demonstrate that this upregulation is due to increased transcription and is dependent on both PI3-kinase and MEK activity. We performed in vitro kinase activity assays and show that BCR-ABL also leads to increased p110 gamma activity and that this activation requires both G protein-coupled receptor and Ras signaling. In addition, by transfection of cells with dominant negative p110 gamma, 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 PI3-kinase isoforms and also demonstrate a previously unreported link between BCR-ABL and p110 gamma.
DOI 10.1074/jbc.M511173200
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