Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 112, Issue 12, Pages 1809-1820Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200320039
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Funding
- NATIONAL CANCER INSTITUTE [R01CA084254, R01CA016303] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI044157] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA016303, R01 CA16303, R01 CA084254, R01 CA84254] Funding Source: Medline
- NIAID NIH HHS [R01 AI44157] Funding Source: Medline
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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 wildtype 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.
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