Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene

Xueping Qu, Jie Yu, Govind Bhagat, Norihiko Furuya, Hanina Hibshoosh, Andrea Troxel, Jeffrey Rosen, Eeva Liisa Eskelinen, Noboru Mizushima, Yoshinori Ohsumi, Giorgio Cattoretti, Beth Levine

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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.

Original languageEnglish (US)
Pages (from-to)1809-1820
Number of pages12
JournalJournal of Clinical Investigation
Volume112
Issue number12
DOIs
StatePublished - Dec 2003

ASJC Scopus subject areas

  • Medicine(all)

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    Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E. L., Mizushima, N., Ohsumi, Y., Cattoretti, G., & Levine, B. (2003). Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. Journal of Clinical Investigation, 112(12), 1809-1820. https://doi.org/10.1172/JCI20039