Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.
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.
Qu
Xueping
X
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Yu
Jie
J
Bhagat
Govind
G
Furuya
Norihiko
N
Hibshoosh
Hanina
H
Troxel
Andrea
A
Rosen
Jeffrey
J
Eskelinen
Eeva-Liisa
EL
Mizushima
Noboru
N
Ohsumi
Yoshinori
Y
Cattoretti
Giorgio
G
Levine
Beth
B
D000483:Alleles; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy; D000071186:Beclin-1; D015139:Blotting, Southern; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005838:Genotype; D006515:Hepatitis B virus / Q000378:metabolism; D006579:Heterozygote; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D011995:Recombination, Genetic; D013950:Thymus Gland / Q000378:metabolism; D013997:Time Factors
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D017931:DNA Primers; D008565:Membrane Proteins; D011506:Proteins