Promotion of Tumorigenesis by Heterozygous Disruption of the Beclin 1 Autophagy Gene

J Clin Invest. 2003 Dec;112(12):1809-20. doi: 10.1172/JCI20039. Epub 2003 Nov 24.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Apoptosis Regulatory Proteins
  • Autophagy*
  • Beclin-1
  • Blotting, Southern
  • Cell Division
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • DNA Primers / genetics
  • Female
  • Genotype
  • Hepatitis B virus / metabolism
  • Heterozygote*
  • Male
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Models, Genetic
  • Mutation
  • Neoplasms / genetics*
  • Proteins / genetics*
  • Recombination, Genetic
  • Thymus Gland / metabolism
  • Time Factors

Substances

  • Apoptosis Regulatory Proteins
  • BECN1 protein, human
  • Beclin-1
  • Becn1 protein, mouse
  • DNA Primers
  • Membrane Proteins
  • Proteins