p62(dok), a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210(bcr-abl)

Di Cristofano, A., Niki, M., Zhao, M. M., Karnell, F. G., Clarkson, B., Pear, W. S., Van Aelst, L., Pandolfi, P. P. (August 2001) p62(dok), a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210(bcr-abl). Journal of Experimental Medicine, 194 (3). pp. 275-284. ISSN 0022-1007

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Abstract

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 p62dok 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-/-l) 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).

Item Type:	Paper
Uncontrolled Keywords:	cell proliferation signal transduction knockout mast cells thyniocytes CHRONIC MYELOGENOUS LEUKEMIA STIMULATES TYROSINE PHOSPHORYLATION GAP-ASSOCIATED PROTEINS B-CELL RECEPTOR DOCKING PROTEIN BCR-ABL SIGNAL-TRANSDUCTION BONE-MARROW MAST-CELLS KIT-LIGAND
Subjects:	bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Mitogen-activated protein kinase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > G protein > Ras
CSHL Authors:	Van Aelst, Linda Zhao, Mingming
Communities:	CSHL labs > Van Aelst lab
Depositing User:	Matt Covey
Date:	August 2001
Date Deposited:	18 Dec 2013 22:06
Last Modified:	18 Dec 2013 22:06
PMCID:	PMC2193466
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/29099

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