Role of Dok-1 and Dok-2 in leukemia suppression Journal Article
| Authors: | Niki, M.; Di Cristofano, A.; Zhao, M.; Honda, H.; Hirai, H.; Van Aelst, L.; Cordon-Cardo, C.; Pandolfi, P. P. |
| Article Title: | Role of Dok-1 and Dok-2 in leukemia suppression |
| 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 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-p21bcr/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. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; protein expression; leukemia; unclassified drug; myeloproliferative disorder; dna-binding proteins; nonhuman; protein function; cell proliferation; protein analysis; animal cell; mouse; animals; mice; mice, knockout; apoptosis; bone marrow; steady state; map kinase signaling system; animal experiment; enzyme activation; phosphorylation; rna-binding proteins; adaptor proteins, signal transducing; phosphoproteins; guanosine triphosphatase activating protein; hematopoiesis; hematopoietic stem cell; homeostasis; fusion proteins, bcr-abl; knockout mouse; knockout gene; knockout; protein p62; gene expression regulation, leukemic; mitogen-activated protein kinase 1; protein dok 1; protein dok 2; blast crisis; leukemia, myeloid, chronic; priority journal; article; cml leukemogenesis; protein p56; p120 gtpase activating protein |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 200 |
| Issue: | 12 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2004-12-20 |
| Start Page: | 1689 |
| End Page: | 1695 |
| Language: | English |
| DOI: | 10.1084/jem.20041306 |
| PROVIDER: | scopus |
| PMCID: | PMC2211998 |
| PUBMED: | 15611295 |
| DOI/URL: | |
| Notes: | J. Exp. Med. -- Cited By (since 1996):50 -- Export Date: 16 June 2014 -- CODEN: JEMEA -- Source: Scopus |
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