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Disruption of the arf transcriptional activator dmp1 facilitates cell immortalization, ras transformation, and tumorigenesis

Academic Article
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Overview

authors

  • Inoue, K.
  • Wen, R. R.
  • Rehg, J. E.
  • Adachi, M.
  • Cleveland, John
  • Roussel, M. F.
  • Sherr, C. J.

publication date

  • July 2000

journal

  • Genes & Development  Journal

abstract

  • The DMP1 transcription factor induces the ARF tumor suppressor gene in mouse fibroblasts, leading to cell cycle arrest in a p53-dependent manner. We disrupted sequences encoding the DNA-binding domain of DMP1 in mouse embryonic stem cells and derived animals lacking the functional protein. DMP1-null animals are small at birth, and males develop more slowly than their wild-type littermates. Some adult animals exhibit seizures and/or obstuctive uropathy, each of unknown cause. The growth of explanted DMP1-null mouse embryo fibroblasts (MEFs) is progressively retarded as cells are passaged in culture on defined transfer protocols; but, unlike the behavior of normal cells, p19(ARF), Mdm2, and p53 levels remain relatively low and DMP1-null MEFs do not senesce. Whereas the establishment of cell lines from MEFs is usually always accompanied by either p53 or ARF loss of function, continuously passaged DMP1-null cells readily give rise to established 3T3 and 3T9 cell lines that retain wild-type ARF and functional p53 genes. Early-passage DMP1-null cells, like MEFs from either ARF-null or p53-null mice, can be morphologically transformed by oncogenic Ha-Ras (Val-12) alone. Splenic lymphocytes harvested from both DMP1-null and ARF-null mice exhibit enhanced proliferative responses in long-term cultures when stimulated to divide with antibody to CD3 and interleukin-2. Although only 1 of 40 DMP1-null animals spontaneously developed a tumor in the first year of life, neonatal treatment with dimethylbenzanthracene or ionizing radiation induced tumors of various histologic types that were not observed in similarly treated DMP1(+/+) animals. Karyotypic analyses of MEFs and lymphomas from DMP1-null animals revealed pseudodiploid chromosome numbers, consistent with the retention of wild-type p53. Together, these data suggest that ARF function is compromised, but not eliminated, in animals lacking functional DMP1.

subject areas

  • 3T3 Cells
  • Age Factors
  • Animals
  • Cell Division
  • Cells, Cultured
  • DNA, Complementary
  • Female
  • Fibroblasts
  • Gene Library
  • Genotype
  • Heterozygote
  • Humans
  • Interleukin-2
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Genetic
  • Mutagenesis, Site-Directed
  • Neoplasms, Experimental
  • Phenotype
  • Proteins
  • T-Lymphocytes
  • Time Factors
  • Tissue Distribution
  • Transcription Factors
  • Transformation, Genetic
  • Tumor Suppressor Protein p14ARF
  • Tumor Suppressor Protein p53
  • ras Proteins
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Research

keywords

  • ARF
  • DMP1
  • Ras transformation
  • cell senescence
  • p53
  • tumor suppression
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Identity

PubMed Central ID

  • PMC316790

International Standard Serial Number (ISSN)

  • 0890-9369

PubMed ID

  • 10898794
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Additional Document Info

start page

  • 1797

end page

  • 1809

volume

  • 14

issue

  • 14

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