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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells
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p62(dok), a negative regulator of Ras and mitogen-activated protein kinase (MAPK) activity, opposes leukemogenesis by

A Di Cristofano1, M Niki, M Zhao

  • 1Department of Human Genetics, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

The Journal of Experimental Medicine
|August 8, 2001
PubMed

Insights

p62(dok) negatively regulates cell proliferation by downregulating Ras/MAPK signaling. Loss of p62(dok) accelerates BCR-ABL-induced leukemia, indicating its role in opposing oncogenesis.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • p62(dok) is a substrate for oncogenic tyrosine kinases like p210(bcr-abl) and is phosphorylated by various growth factor receptors.
  • The precise biological roles of p62(dok) in normal cellular signaling and BCR-ABL-driven leukemogenesis remain incompletely understood.

Purpose of the Study:

  • To elucidate the function of p62(dok) in growth factor signaling and its impact on BCR-ABL-induced leukemia.
  • To investigate the role of p62(dok) as a negative regulator in cellular proliferation and oncogenic transformation.

Main Methods:

  • Utilized p62(dok)-deficient (p62(dok)-/-) mice to derive hemopoietic and nonhemopoietic cells for functional studies.
  • Assessed cell proliferation, Ras/MAPK pathway activation, apoptosis induction, and leukemia latency following p210(bcr-abl) transduction.

Main Results:

  • Loss of p62(dok) led to increased cell proliferation upon growth factor stimulation and sustained Ras/MAPK activation after growth factor withdrawal.
  • p62(dok) inactivation did not alter apoptosis induced by DNA damage or growth factor deprivation.
  • p62(dok) deficiency significantly shortened the latency of myeloproliferative disease induced by p210(bcr-abl).

Conclusions:

  • p62(dok) functions as a negative regulator of growth factor-induced cell proliferation, partly by downregulating the Ras/MAPK signaling pathway.
  • p62(dok) plays a critical role in opposing p210(bcr-abl)-mediated leukemogenesis.

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