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Gene trap mutagenesis-based forward genetic approach reveals that the tumor suppressor OVCA1 is a component of the biosynthetic pathway of diphthamide on elongation factor 2.

Abstract
OVCA1 is a tumor suppressor identified by positional cloning from chromosome 17p13.3, a hot spot for chromosomal aberration in breast and ovarian cancers. It has been shown that expression of OVCA1 is reduced in some tumors and that it regulates cell proliferation, embryonic development, and tumorigenesis. However, the biochemical function of OVCA1 has remained unknown. Recently, we isolated a novel mutant resistant to diphtheria toxin and Pseudomonas exotoxin A from the gene trap insertional mutants library of Chinese hamster ovary cells. In this mutant, the Ovca1 gene was disrupted by gene trap mutagenesis, and this disruption well correlated with the toxin-resistant phenotype. We demonstrated direct evidence that the tumor suppressor OVCA1 is a component of the biosynthetic pathway of diphthamide on elongation factor 2, the target of bacterial ADP-ribosylating toxins. A functional genetic approach utilizing the random gene trap mutants library of mammalian cells should become a useful strategy to identify the genes responsible for specific phenotypes.
AuthorsYoshitaka Nobukuni, Kenji Kohno, Kiyoshi Miyagawa
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 280 Issue 11 Pg. 10572-7 (Mar 18 2005) ISSN: 0021-9258 [Print] United States
PMID15637051 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Coloring Agents
  • DNA, Complementary
  • DPH1 protein, human
  • DPH2 protein, human
  • Diphtheria Toxin
  • Minor Histocompatibility Antigens
  • Peptide Elongation Factor 2
  • Proteins
  • Tetrazolium Salts
  • Thiazoles
  • Toxins, Biological
  • Tumor Suppressor Proteins
  • Histidine
  • Adenosine Diphosphate
  • diphthamide
  • thiazolyl blue
Topics
  • Adenosine Diphosphate (metabolism)
  • Animals
  • Base Sequence
  • Blotting, Southern
  • Blotting, Western
  • CHO Cells
  • Coloring Agents (pharmacology)
  • Cricetinae
  • DNA, Complementary (metabolism)
  • Diphtheria Toxin (pharmacology)
  • Dose-Response Relationship, Drug
  • Genes, Tumor Suppressor
  • Genetic Techniques
  • Histidine (analogs & derivatives, chemistry, pharmacology)
  • Humans
  • Mice
  • Minor Histocompatibility Antigens
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation
  • Peptide Elongation Factor 2 (genetics)
  • Phenotype
  • Plasmids (metabolism)
  • Polymerase Chain Reaction
  • Proteins (genetics)
  • Retroviridae (genetics)
  • Sequence Homology, Nucleic Acid
  • Tetrazolium Salts (pharmacology)
  • Thiazoles (pharmacology)
  • Toxins, Biological
  • Tumor Suppressor Proteins (genetics)

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