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

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Autophagy
Carcinogenesis
Genes
Neoplasms
Beclin-1
Tumor Suppressor Genes
Hepatitis B virus
Organelles
Ovarian Neoplasms
Prostatic Neoplasms
Alleles
Cell Proliferation
Breast Neoplasms
Mutation
Growth
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

In: Journal of Clinical Investigation, Vol. 112, No. 12, 12.2003, p. 1809-1820.

Research output: Contribution to journalArticle

Qu, X, Yu, J, Bhagat, G, Furuya, N, Hibshoosh, H, Troxel, A, Rosen, J, Eskelinen, EL, 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, vol. 112, no. 12, pp. 1809-1820. https://doi.org/10.1172/JCI200320039
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. / Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. In: Journal of Clinical Investigation. 2003 ; Vol. 112, No. 12. pp. 1809-1820.
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