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Original Article

^a Department of Human Genetics, Molecular Biology Program
^b Department of Medicine, Molecular Pharmacology and Therapeutics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
^c Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
^d Department of Pathology and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104
Department of Human Genetics, Box 110 Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.212-717-3102212-639-6168

p-pandolfi{at}ski.mskcc.org

p62^dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210^bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62^dok in normal cell signaling as well as in p210^bcr-abl leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62^dok–^/– mice, that the loss of p62^dok results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62^dok–^/– cells after the removal of growth factor. However, p62^dok inactivation does not affect DNA damage and growth factor deprivation–induced apoptosis. Furthermore, p62^dok inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210^bcr-abl in bone marrow cells. These data indicate that p62^dok acts as a negative regulator of growth factor–induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62^dok can oppose leukemogenesis by p210^bcr-abl.

Key Words: cell proliferation • signal transduction • knockout • mast cells • thymocytes

Abbreviations used in this paper: BMMC, bone marrow–derived mast cell; CML, chronic myelogenous leukemia; EGF, epidermal growth factor; ES, embryonic stem; KL, kit ligand; MAPK, mitogen-activated protein kinase; PDGF, platelet-derived growth factor; PEF, primary embryonic fibroblast.

© 2001 The Rockefeller University Press

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