Role of Dok-1 and Dok-2 in leukemia suppression

Niki, M., Di Cristofano, A., Zhao, M., Honda, H., Hirai, H., Van Aelst, L., Cordon-Cardo, C., Pandolfi, P. P. (December 2004) Role of Dok-1 and Dok-2 in leukemia suppression. J Exp Med, 200 (12). pp. 1689-95.

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URL: http://www.pubmedcentral.nih.gov/articlerender.fcg...
DOI: 10.1084/jem.20041306

Abstract

Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210bcr/abl oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210bcr/abl substrates have been identified, their relevance in the pathogenesis of the disease is unclear. We have identified a family of proteins, Dok (downstream of tyrosine kinase), coexpressed in hematopoietic progenitor cells. Members of this family such as p62dok (Dok-1) and p56dok-2 (Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210bcr/abl as well as receptor and nonreceptor tyrosine kinases. Here, we report the generation and characterization of single and double Dok-1 or Dok-2 knockout (KO) mutants. Single KO mice displayed normal steady-state hematopoiesis. By contrast, concomitant Dok-1 and Dok-2 inactivation resulted in aberrant hemopoiesis and Ras/MAP kinase activation. Strikingly, all Dok-1/Dok-2 double KO mutants spontaneously developed transplantable CML-like myeloproliferative disease due to increased cellular proliferation and reduced apoptosis. Furthermore, Dok-1 or Dok-2 inactivation markedly accelerated leukemia and blastic crisis onset in Tec-p210bcr/abl transgenic mice known to develop, after long latency, a myeloproliferative disorder resembling human CML. These findings unravel the critical and unexpected role of Dok-1 and Dok-2 in tumor suppression and control of the hematopoietic compartment homeostasis.

Item Type: Paper
Additional Information:
Uncontrolled Keywords: Adaptor Proteins Signal Transducing genetics metabolism Animals Apoptosis genetics Blast Crisis genetics metabolism pathology Bone Marrow metabolism pathology Cell Proliferation DNA-Binding Proteins genetics metabolism Fusion Proteins bcr-abl genetics metabolism Gene Expression Regulation Leukemic genetics Hematopoiesis genetics Homeostasis genetics Leukemia Myelogenous Chronic BCR-ABL Positive genetics metabolism pathology MAP Kinase Signaling System genetics Mice Mice Knockout Mitogen-Activated Protein Kinase 1 metabolism Phosphoproteins genetics metabolism Phosphorylation RNA-Binding Proteins genetics metabolism p120 GTPase Activating Protein metabolism
Subjects: diseases & disorders > cancer > cancer types > leukemia
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase
Communities: CSHL labs > Van Aelst lab
Depositing User: CSHL Librarian
Date: 20 December 2004
Date Deposited: 31 Jan 2012 16:50
Last Modified: 31 Jan 2012 16:50
PMCID: PMC2211998
URI: http://repository.cshl.edu/id/eprint/22450

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