title: Genetic inhibition of autophagy promotes p53 loss-of-heterozygosity and tumorigenesis.
abstract: Autophagy is an evolutionarily conserved lysosomal degradation pathway that plays an essential role in enabling eukaryotic organisms to adapt to nutrient deprivation and other forms of environmental stress. In metazoan organisms, autophagy is essential for differentiation and normal development; however, whether the autophagy pathway promotes or inhibits tumorigenesis is controversial, and the possible mechanisms linking defective autophagy to cancer remain unclear. To determine if autophagy is important for tumor suppression, we inhibited autophagy in transgenic zebrafish via stable, tissue-specific expression of a dominant-negative autophagy protein Atg5K130R. In heterozygous tp53 mutants, expression of dominant-negative atg5K130R increased tumor incidence and decreased tumor latency compared to non-transgenic heterozygous tp53 mutant controls. In a tp53-deficient background, Tg(mitfa:atg5K130R) mutantsdeveloped malignant peripheral nerve sheath tumors (MPNSTs), neuroendocrine tumors and small-cell tumors. Expression of a Sox10-dependent GFP transgene in the tumors demonstrated their origin from neural crest cells, lending support to a model in which mitfa-expressing cells can arise from sox10+ Schwann cell precursors. Tumors from the transgenic animals exhibited increased DNA damage and loss-of-heterozygosity of tp53. Taken together, our data indicate that genetic inhibition of autophagy promotes tumorigenesis in tp53 mutant zebrafish, and suggest a possible role for autophagy in the regulation of genome stability during oncogenesis.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Eunmyong
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Tucker
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Center for Autophagy Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Amatruda
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D019656:Loss of Heterozygosity; D009154:Mutation; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism; D009432:Neural Crest / Q000378:metabolism / Q000473:pathology; D055757:SOXE Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C572697:Atg5 protein, zebrafish; D000071187:Autophagy-Related Protein 5; D055757:SOXE Transcription Factors; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C442229:sox10 protein, zebrafish; D049452:Green Fluorescent Proteins
keywords: MPNST; loss-of-heterozygosity; p53; zebrafish; Autophagy