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 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.This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org.

Autophagy and AML—food for thought

“…In these experiments the autophagy gene Atg5 is acting as tumor suppressor, and haploinsufficiency is enough to remove this tumor suppressor activity. Even if Atg5 (or Atg7) mutations are rarely described in AML (or rarely identified in sequence databases such as COSMIC 3 ), the findings of this paper are entirely consistent with a study from Qu et al 4 that shows that beclin-1 is also a haploinsufficient tumor-suppressor gene. Both studies support the hypothesis that reduced autophagic activity contributes to the oncogenic functions of more established mutations in cancer, including in the PI3K/AKT/mTor pathway.…”

Stress and mTORture signaling

“…Autophagy may reflect (1) a protective mechanism for cell survival acting as safeguard to remove damaged polypeptides and organelles or (2) a proapoptotic process to get rid of compromised cells. The finding that beclin1, an essential gene for autophagy, is deleted in a large number of cancer cell lines (Aita et al, 1999;Liang et al, 1999) and that heterozygosity for the beclin1 locus caused a high number of spontaneous tumors in mice suggests that it acts as a tumor suppressor (Qu et al, 2003;Yue et al, 2003). However, the dual role for autophagy both as a cell-protective and cell-destructive mechanism hampers to draw a clearcut conclusion about its tumor-suppressing role (Lum et al, 2005).…”

Macroautophagy versus mitochondrial autophagy: a question of fate?

“…10 Beclin1 À/À mice die during embryogenesis, and although Beclin1 þ /À heterozygotes are viable, they exhibit an increased incidence of tumors. 50,51 Autophagy can promote cell survival in mammalian cells…”