Negative Regulator of Ras and Mitogen - activated Protein Kinase ( MAPK ) Activity , Opposes Leukemogenesis by p 210 bcr - abl Antonio

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 .