p62dok, a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210bcr-abl Journal Article
| Authors: | Di Cristofano, A.; Niki, M.; Zhao, M.; Karnell, F. G.; Clarkson, B.; Pear, W. S.; Van Aelst, L.; Pandolfi, P. P. |
| Article Title: | p62dok, a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210bcr-abl |
| 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. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; unclassified drug; myeloproliferative disorder; dna-binding proteins; nonhuman; cell proliferation; animal cell; mouse mutant; animals; mice; mice, knockout; dna damage; cells, cultured; gene targeting; cell division; animal experiment; mitogenesis; enzyme activation; enzyme activity; chronic myeloid leukemia; rna-binding proteins; enzyme regulation; leukemogenesis; phosphoproteins; bcr abl protein; ras proteins; sequence homology; mitogen-activated protein kinases; fusion proteins, bcr-abl; knockout; protein p62; mast cells; thymocytes; leukemia, myeloid, chronic; humans; male; female; priority journal; article; protein p62 dok |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 194 |
| Issue: | 3 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2001-08-06 |
| Start Page: | 275 |
| End Page: | 284 |
| Language: | English |
| DOI: | 10.1084/jem.194.3.275 |
| PUBMED: | 11489947 |
| PROVIDER: | scopus |
| PMCID: | PMC2193466 |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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