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- Title
Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.
- Authors
Qu, Xueping; Yu, Jie; Bhagat, Govind; Furuya, Norihiko; Hibshoosh, Hanina; Troxel, Andrea; Rosen, Jeffrey; Eskelinen, Eeva-Liisa; Mizushima, Noboru; Ohsumi, Yoshinori; Cattoretti, Giorgio; Levine, Beth
- 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
The Journal of clinical investigation, 2003, Vol 112, Issue 12, p1809
- ISSN
0021-9738
- Publication type
Journal Article
- DOI
10.1172/JCI20039