Niki, M., Di Cristofano, A., Zhao, M. 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. Journal of Experimental Medicine, 200 (12). pp. 1689-1695. ISSN 0022-1007
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Abstract
Chronic myelogenous leukemia (CML) is characterized by the presence of the chimeric p210(bcr/abl) oncoprotein that shows elevated and constitutive protein tyrosine kinase activity relative to the normal c-abl tyrosine kinase. Although several p210(bcr/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 p62(dok) (Dok-1) and p56(dok-2) (Dok-2) associate with the p120 rasGTPase-activating protein (rasGAP) upon phosphorylation by p210(bcr/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-p210(bcr/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 |
|---|---|
| Uncontrolled Keywords: | cell proliferation apoptosis knockout CML leukemogenesis signal transduction NEGATIVE REGULATION DOCKING PROTEIN P62(DOK) KINASE FAMILY MICE P56(DOK-2) CELLS RAS |
| Subjects: | diseases & disorders > cancer diseases & disorders > cancer > cancer types > leukemia bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Mitogen-activated protein kinase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase |
| CSHL Authors: | |
| Communities: | CSHL labs > Van Aelst lab |
| Depositing User: | Matt Covey |
| Date: | December 2004 |
| Date Deposited: | 18 Dec 2013 22:12 |
| Last Modified: | 18 Dec 2013 22:12 |
| PMCID: | PMC2211998 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/29094 |
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