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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 RIS Download

Mesh terms: Alleles | Animals | Apoptosis Regulatory Proteins | Autophagy | Beclin-1 | 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

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA084254
  • Agency: NCI NIH HHS, Id: R01 CA16303
  • Agency: NCI NIH HHS, Id: R01 CA84254
  • Agency: NIAID NIH HHS, Id: R01 AI44157
  • Agency: NCI NIH HHS, Id: R01 CA016303

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