p62dok, a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210bcr-abl

A. Di Cristofano, M. Niki, M. Zhao, F. G. Karnell, B. Clarkson, W. S. Pear, L. Van Aelst, P. P. Pandolfi

Research output: Contribution to journalArticlepeer-review

97 Scopus citations

Abstract

p62dok has been identified as a substrate of many oncogenic tyrosine kinases such as the chronic myelogenous leukemia (CML) chimeric p210bcr-abl oncoprotein. It is also phosphorylated upon activation of many receptors and cytoplamic tyrosine kinases. However, the biological functions of p62dok in normal cell signaling as well as in p210bcr-abl leukemogenesis are as yet not fully understood. Here we show, in hemopoietic and nonhemopoietic cells derived from p62dok-/- mice, that the loss of p62dok results in increased cell proliferation upon growth factor treatment. Moreover, Ras and mitogen-activated protein kinase (MAPK) activation is markedly sustained in p62dok-/- cells after the removal of growth factor. However, p62dok inactivation does not affect DNA damage and growth factor deprivation-induced apoptosis. Furthermore, p62dok inactivation causes a significant shortening in the latency of the fatal myeloproliferative disease induced by retroviral-mediated transduction of p210bcr-abl in bone marrow cells. These data indicate that p62dok acts as a negative regulator of growth factor-induced cell proliferation, at least in part through downregulating Ras/MAPK signaling pathway, and that p62dok can oppose leukemogenesis by p210bcr-abl.

Original languageEnglish (US)
Pages (from-to)275-284
Number of pages10
JournalJournal of Experimental Medicine
Volume194
Issue number3
DOIs
StatePublished - Aug 6 2001
Externally publishedYes

Keywords

  • Cell proliferation
  • Knockout
  • Mast cells
  • Signal transduction
  • Thymocytes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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