title: Dok1 and SHIP act as negative regulators of v-Abl-induced pre-B cell transformation, proliferation and Ras/Erk activation.
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.
authors.affiliation: Department of Medicine, Integrated Program in Cellular, Columbia University College of Physicians and Surgeons, New York, New York, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Oki
authors.forename: André
authors.initials: A
authors.lastname: Limnander
authors.forename: Pin Mei
authors.initials: PM
authors.lastname: Yao
authors.forename: Masaru
authors.initials: M
authors.lastname: Niki
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Paul B
authors.initials: PB
authors.lastname: Rothman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001549:Benzamides; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors; D015973:Gene Expression Regulation, Leukemic; D000068877:Imatinib Mesylate; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D016374:Oncogene Proteins v-abl / Q000235:genetics / Q000502:physiology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010879:Piperazines; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D011743:Pyrimidines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C096856:FTI 277; D016374:Oncogene Proteins v-abl; D010750:Phosphoproteins; D010879:Piperazines; D011743:Pyrimidines; D016601:RNA-Binding Proteins; D000068877:Imatinib Mesylate; D008715:Methionine; D051231:Farnesyltranstransferase; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D018631:ras Proteins