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Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.

Malignant cells often display defects in autophagy, an evolutionarily conserved pathway for degrading long-lived proteins and cytoplasmic organelles. However, as yet, there is no genetic evidence for a role of autophagy genes in tumor suppression. The beclin 1 autophagy gene is monoallelically deleted in 40-75% of cases of human sporadic breast, ovarian, and prostate cancer. Therefore, we used a targeted mutant mouse model to test the hypothesis that monoallelic deletion of beclin 1 promotes tumorigenesis. Here we show that heterozygous disruption of beclin 1 increases the frequency of spontaneous malignancies and accelerates the development of hepatitis B virus-induced premalignant lesions. Molecular analyses of tumors in beclin 1 heterozygous mice show that the remaining wild-type allele is neither mutated nor silenced. Furthermore, beclin 1 heterozygous disruption results in increased cellular proliferation and reduced autophagy in vivo. These findings demonstrate that beclin 1 is a haplo-insufficient tumor-suppressor gene and provide genetic evidence that autophagy is a novel mechanism of cell-growth control and tumor suppression. Thus, mutation of beclin 1 or other autophagy genes may contribute to the pathogenesis of human cancers.

Pubmed ID: 14638851


  • Qu X
  • Yu J
  • Bhagat G
  • Furuya N
  • Hibshoosh H
  • Troxel A
  • Rosen J
  • Eskelinen EL
  • Mizushima N
  • Ohsumi Y
  • Cattoretti G
  • Levine B


The Journal of clinical investigation

Publication Data

December 17, 2003

Associated Grants

  • Agency: NIAID NIH HHS, Id: R01 AI44157
  • Agency: NCI NIH HHS, Id: R01 CA16303
  • Agency: NCI NIH HHS, Id: R01 CA84254

Mesh Terms

  • Alleles
  • Animals
  • Apoptosis Regulatory Proteins
  • Autophagy
  • Blotting, Southern
  • Cell Division
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • DNA Primers
  • Female
  • Genotype
  • Hepatitis B virus
  • Heterozygote
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Models, Genetic
  • Mutation
  • Neoplasms
  • Proteins
  • Recombination, Genetic
  • Thymus Gland
  • Time Factors