Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene
Xueping Qu, … , Giorgio Cattoretti, Beth Levine
Xueping Qu, … , Giorgio Cattoretti, Beth Levine
Published December 15, 2003
Citation Information: J Clin Invest. 2003;112(12):1809-1820. https://doi.org/10.1172/JCI20039.
View: Text | PDF
Article Oncology Article has an altmetric score of 8

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

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.

Authors

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

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Targeted disruption of beclin 1 in mice. (a) Restriction maps of the wil...
Targeted disruption of beclin 1 in mice. (a) Restriction maps of the wild-type beclin 1 allele (top), the beclin 1 targeting vector (middle), and the predicted targeted beclin 1 allele (bottom). Restriction sites are as follows: EcoRI (E), HindIII (H). The targeting construct contains a cassette with the neomycin resistance gene (Neo) that has replaced exons 1 and 2 of the beclin 1 gene. “X” denotes regions of homologous recombination between the targeting vector and wild-type allele. The beclin 1 genomic fragment used as a 3′ external probe for Southern blot analysis is indicated by a solid black box. Expected sizes of the EcoRI fragments that hybridize with the probe are indicated. (b) Southern blot analysis of genomic DNA from beclin 1+/+ and beclin 1+/– ES cells and mouse tails. The DNA was digested with EcoRI and hybridized with the probe indicated in a. The sizes of wild-type (WT) and disrupted (KO) alleles are shown. (c) PCR genotyping of genomic DNA from beclin 1+/– and beclin 1+/+ ES cells and mouse tail DNA. Primers 1 and 2 in a were used to detect the wild-type allele, and primers 1 and 3 in a were used to detect the knockout allele. (d) Western blot analysis of Beclin 1 protein expression in beclin 1+/+ and beclin 1+/– ES cells and mouse lung samples. Sizes of Beclin 1 isoforms and an actin control are indicated on the right. Lung lysates were prepared from 2-month-old mice. Similar results were observed for samples from six different mice of each genotype.