p62dok, a Negative Regulator of Ras and Mitogen-activated Protein Kinase (MAPK) Activity, Opposes Leukemogenesis by p210bcr-abl

doi:10.1084/jem.194.3.275

Published online 30 July 2001. doi:10.1084/jem.194.3.275

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© The Rockefeller University Press, 0022-1007/2001/8/275/ $5.00
The Journal of Experimental Medicine, Volume 194, Number 3, August 6, 2001 275-284

Original Article

p62^dok, a Negative Regulator of Ras and Mitogen-activated Protein Kinase (MAPK) Activity, Opposes Leukemogenesis by p210^bcr-abl

Antonio Di Cristofano^a, Masaru Niki^a, Mingming Zhao^c, Fredrick G. Karnell^d, Bayard Clarkson^b, Warren S. Pear^d, Linda Van Aelst^c, and Pier Paolo Pandolfi^a
^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

Correspondence to: Pier Paolo Pandolfi, Department of Human Genetics, Box 110 Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021. Tel:212-639-6168 Fax:212-717-3102 E-mail:p-pandolfi{at}ski.mskcc.org.

p62^dok has been identified as a substrate of many oncogenictyrosine kinases such as the chronic myelogenous leukemia (CML)chimeric p210^bcr-abl oncoprotein. It is also phosphorylatedupon activation of many receptors and cytoplamic tyrosine kinases.However, the biological functions of p62^dok in normal cell signalingas well as in p210^bcr-abl leukemogenesis are as yet not fullyunderstood. Here we show, in hemopoietic and nonhemopoieticcells derived from p62^dok-^/- mice, that the loss of p62^dok resultsin increased cell proliferation upon growth factor treatment.Moreover, Ras and mitogen-activated protein kinase (MAPK) activationis markedly sustained in p62^dok-^/- cells after the removal ofgrowth factor. However, p62^dok inactivation does not affectDNA damage and growth factor deprivation–induced apoptosis.Furthermore, p62^dok inactivation causes a significant shorteningin the latency of the fatal myeloproliferative disease inducedby retroviral-mediated transduction of p210^bcr-abl in bone marrowcells. These data indicate that p62^dok acts as a negative regulatorof growth factor–induced cell proliferation, at leastin part through downregulating Ras/MAPK signaling pathway, andthat p62^dok can oppose leukemogenesis by p210^bcr-abl.

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

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