Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
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Open Access
- 15 December 2003
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 112 (12), 1809-1820
- https://doi.org/10.1172/jci20039
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.Keywords
This publication has 68 references indexed in Scilit:
- Convergence of Multiple Autophagy and Cytoplasm to Vacuole Targeting Components to a Perivacuolar Membrane Compartment Prior tode Novo Vesicle FormationPublished by Elsevier BV ,2002
- Premalignant lesions of hepatocellular carcinoma: pathologic viewpointJournal of Hepato-Biliary-Pancreatic Surgery, 2000
- LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processingThe EMBO Journal, 2000
- Tor, a Phosphatidylinositol Kinase Homologue, Controls Autophagy in YeastPublished by Elsevier BV ,1998
- Isolation of autophagocytosis mutants of Saccharomyces cerevisiaeFEBS Letters, 1994
- Regulation of lysosomal autophagy in transformed and non-transformed mouse fibroblasts under several growth conditions*1Experimental Cell Research, 1984
- Role of the vacuolar apparatus in augmented protein degradation in cultured fibroblastsJournal of Cellular Physiology, 1978
- Effect of the growth state on protein turnover in two lines of cultured BHK cellsJournal of Cellular Physiology, 1977
- Reduced rates of proteolysis in transformed cellsNature, 1977
- Mutation and Cancer: Statistical Study of RetinoblastomaProceedings of the National Academy of Sciences of the United States of America, 1971