Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
Xueping Qu,Jie Yu,Govind Bhagat,Norihiko Furuya,Hanina Hibshoosh,Andrea B. Troxel,Jeffrey M. Rosen,Eeva-Liisa Eskelinen,Noboru Mizushima,Yoshinori Ohsumi,Giorgio Cattoretti,Beth Levine +11 more
TLDR
It is shown that heterozygous disruption of beclin 1 increases the frequency of spontaneous malignancies and accelerates the development of hepatitis B virus-induced premalignant lesions, providing genetic evidence that autophagy is a novel mechanism of cell-growth control and tumor suppression.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.read more
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