Abstract
The v-Abl tyrosine kinase activates several signaling pathways during transformation of bone marrow cells in mice. Because the SH2-containing inositol 5'-phosphatase (SHIP) and Downstream of tyrosine kinase 1 (Dok1) have been shown to interact with Abl, the effect of SHIP and Dok1 deficiency on v-Abl transformation was investigated. Bone marrow cells from either Dok1- or SHIP-deficient mice are more susceptible to transformation by v-Abl. v-Abl-transformed preB cells from these knockout mice show Abl kinase-dependent hyperproliferation and moderate resistance to apoptosis. Elevated activation of Ras, Raf-1, and Erk, but not of Akt, was observed in either SHIP(-/-) or Dok1(-/-) v-Abl-transformed cells. This activation is sensitive to treatment with STI571. Furthermore, treatment of these cells with either a farnesyltransferase inhibitor or a MEK1/2 inhibitor abrogates the increased proliferation of SHIP(-/-) or Dok1(-/-) cells in a dose-dependent manner. Complementation of SHIP(-/-) or Dok1(-/-) cells abrogates their hyperproliferation and intracellular Erk activation. These data indicate that both SHIP and Dok1 functionally regulate the activation of Ras-Erk pathway by v-Abl and affect the mitogenic activity of v-Abl transformed bone marrow cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / genetics
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Benzamides
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / pathology
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Bone Marrow Cells / physiology
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Cell Line
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Cell Proliferation
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Cell Transformation, Neoplastic / genetics*
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Cell Transformation, Neoplastic / pathology
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Dose-Response Relationship, Drug
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Enzyme Activation / genetics
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Farnesyltranstransferase / antagonists & inhibitors
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Gene Expression Regulation, Leukemic
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Imatinib Mesylate
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MAP Kinase Kinase 1 / antagonists & inhibitors
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MAP Kinase Kinase 2 / antagonists & inhibitors
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Methionine / analogs & derivatives
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Methionine / pharmacology
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Mice
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Oncogene Proteins v-abl / genetics
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Oncogene Proteins v-abl / physiology*
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
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Phosphoproteins / deficiency
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Phosphoproteins / genetics
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Phosphoproteins / physiology*
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Phosphoric Monoester Hydrolases / deficiency
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Phosphoric Monoester Hydrolases / genetics
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Phosphoric Monoester Hydrolases / physiology*
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Piperazines
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / physiopathology*
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Pyrimidines / pharmacology
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / physiology*
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Signal Transduction / genetics
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Benzamides
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DNA-Binding Proteins
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Dok1 protein, mouse
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FTI 277
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Oncogene Proteins v-abl
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Phosphoproteins
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Piperazines
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Pyrimidines
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RNA-Binding Proteins
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Imatinib Mesylate
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Methionine
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Farnesyltranstransferase
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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Map2k1 protein, mouse
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Map2k2 protein, mouse
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Phosphoric Monoester Hydrolases
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INPPL1 protein, human
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Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
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ras Proteins