Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.
Qu, Xueping 1; Yu, Jie 1; Bhagat, Govind 2; Furuya, Norihiko 1; Hibshoosh, Hanina 2; Troxel, Andrea 3; Rosen, Jeffrey 4; Eskelinen, Eeva-Liisa 5; Mizushima, Noboru 6,7; Ohsumi, Yoshinori 6; Cattoretti, Giorgio 2,8; Levine, Beth 1
[Article]
Journal of Clinical Investigation.
112(12):1809-1820, December 2003.
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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.
Copyright (C) 2003 The American Society for Clinical Investigation, Inc.