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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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: | https://repository.cshl.edu/id/eprint/22450 |
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