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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.

SUBMITTER: Qu X

PROVIDER: S-EPMC297002 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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

Qu Xueping X 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

The Journal of clinical investigation 20031124 12

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 tum ...[more]

PMID: 14638851

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Project description:Nine neurodegenerative diseases are caused by expanded polyglutamine (polyQ) tracts in different proteins, such as huntingtin in Huntington's disease and ataxin 3 in spinocerebellar ataxia type 3 (SCA3). Age at onset of disease decreases with increasing polyglutamine length in these proteins and the normal length also varies. PolyQ expansions drive pathogenesis in these diseases, as isolated polyQ tracts are toxic, and an N-terminal huntingtin fragment comprising exon 1, which occurs in vivo as a result of alternative splicing, causes toxicity. Although such mutant proteins are prone to aggregation, toxicity is also associated with soluble forms of the proteins. The function of the polyQ tracts in many normal cytoplasmic proteins is unclear. One such protein is the deubiquitinating enzyme ataxin 3 (refs 7, 8), which is widely expressed in the brain. Here we show that the polyQ domain enables wild-type ataxin 3 to interact with beclin 1, a key initiator of autophagy. This interaction allows the deubiquitinase activity of ataxin 3 to protect beclin 1 from proteasome-mediated degradation and thereby enables autophagy. Starvation-induced autophagy, which is regulated by beclin 1, was particularly inhibited in ataxin-3-depleted human cell lines and mouse primary neurons, and in vivo in mice. This activity of ataxin 3 and its polyQ-mediated interaction with beclin 1 was competed for by other soluble proteins with polyQ tracts in a length-dependent fashion. This competition resulted in impairment of starvation-induced autophagy in cells expressing mutant huntingtin exon 1, and this impairment was recapitulated in the brains of a mouse model of Huntington's disease and in cells from patients. A similar phenomenon was also seen with other polyQ disease proteins, including mutant ataxin 3 itself. Our data thus describe a specific function for a wild-type polyQ tract that is abrogated by a competing longer polyQ mutation in a disease protein, and identify a deleterious function of such mutations distinct from their propensity to aggregate.

Project description:Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcomes amongst lung cancer patients suggesting the importance of other pathways. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well defined role in colon and skin cancer but its role in lung cancer remains unclear. We show that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult lung does not promote tumor development by itself. However, activation of Wnt/β- catenin signaling leads to a dramatic increase in tumor formation both in overall tumor number and size compared to KrasG12D alone. We show that activation of Wnt/β- catenin signaling significantly alters the KrasG12D tumor phenotype resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This is associated with a decrease in E- cadherin expression at the cell surface which may increase metastasis in Wnt/β-catenin signaling positive tumors. Together, these data suggest that activation of Wnt/β-catenin signaling in combination with other oncogenic pathways in lung epithelium may lead to a more aggressive phenotype due to the imposition of an embryonic distal progenitor phenotype accompanied by decreased E-cadherin expression. We performed microarray analysis of control murine lung, CC10-cre:KrasG12D, and CC10-cre:Ctnnb1ex3flox:LSL-KrasG12D double mutant micro-dissected murine lung tumors to determine their transcriptional phenotype. Lungs of five-month-old mice were PBS inflated and all the tumors in each lobe were dissected. The total number of tumors obtained from three out of the 5 pulmonar lobes of each animal was called a sample the other two lobes were saved in case there were problems and the array needed to be repeated. Trizol was used to isolate RNA for microarray analysis. Samples & Genotypes: control murine lung n=2 animals, CC10-cre:KrasG12D n=2 animals, and CC10-cre:Ctnnb1ex3flox:LSL-KrasG12D n=2 animals.

Dataset Information

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

Publications

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

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