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

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

Research output: Contribution to journalArticle

95 Citations (Scopus)

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

Fingerprint

Mitogen-Activated Protein Kinases
Intercellular Signaling Peptides and Proteins
Cell Proliferation
Oncogene Proteins
Receptor Protein-Tyrosine Kinases
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Bone Marrow Cells
Protein-Tyrosine Kinases
DNA Damage
Down-Regulation
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

p62dok, a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210bcr-abl. / Di Cristofano, Antonio; Niki, M.; Zhao, M.; Karnell, F. G.; Clarkson, B.; Pear, W. S.; Van Aelst, L.; Pandolfi, P. P.

In: Journal of Experimental Medicine, Vol. 194, No. 3, 06.08.2001, p. 275-284.

Research output: Contribution to journalArticle

Di Cristofano, Antonio ; Niki, M. ; Zhao, M. ; Karnell, F. G. ; Clarkson, B. ; Pear, W. S. ; Van Aelst, L. ; Pandolfi, P. P. / p62dok, a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210bcr-abl. In: Journal of Experimental Medicine. 2001 ; Vol. 194, No. 3. pp. 275-284.
@article{9ebc4b8ea802425ebf714bedec0e1a96,
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 = "Cell proliferation, Knockout, Mast cells, Signal transduction, Thymocytes",
author = "{Di Cristofano}, Antonio and M. Niki and M. Zhao and Karnell, {F. G.} and B. Clarkson and Pear, {W. S.} and {Van Aelst}, L. and Pandolfi, {P. P.}",
year = "2001",
month = "8",
day = "6",
doi = "10.1084/jem.194.3.275",
language = "English (US)",
volume = "194",
pages = "275--284",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "3",

}

TY - JOUR

T1 - p62dok, a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by p210bcr-abl

AU - Di Cristofano, Antonio

AU - Niki, M.

AU - Zhao, M.

AU - Karnell, F. G.

AU - Clarkson, B.

AU - Pear, W. S.

AU - Van Aelst, L.

AU - Pandolfi, P. P.

PY - 2001/8/6

Y1 - 2001/8/6

N2 - 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.

AB - 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.

KW - Cell proliferation

KW - Knockout

KW - Mast cells

KW - Signal transduction

KW - Thymocytes

UR - http://www.scopus.com/inward/record.url?scp=0035817343&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035817343&partnerID=8YFLogxK

U2 - 10.1084/jem.194.3.275

DO - 10.1084/jem.194.3.275

M3 - Article

C2 - 11489947

AN - SCOPUS:0035817343

VL - 194

SP - 275

EP - 284

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 3

ER -