ZFIN ID: ZDB-PUB-160923-5
Genetic inhibition of autophagy promotes p53 loss-of-heterozygosity and tumorigenesis
Lee, E., Wei, Y., Zou, Z., Tucker, K., Rakheja, D., Levine, B., Amatruda, J.F.
Date: 2016
Source: Oncotarget   7(42): 67919-67933 (Journal)
Registered Authors: Amatruda, James F., Lee, Eunmyong, Tucker, Kathryn
Keywords: MPNST, autophagy, loss-of-heterozygosity, p53, zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Autophagy/genetics*
  • Autophagy-Related Protein 5/genetics
  • Autophagy-Related Protein 5/metabolism
  • Cell Transformation, Neoplastic/genetics*
  • Cell Transformation, Neoplastic/metabolism
  • DNA Damage
  • Green Fluorescent Proteins/genetics
  • Green Fluorescent Proteins/metabolism
  • Loss of Heterozygosity*
  • Mutation
  • Nerve Sheath Neoplasms/genetics
  • Nerve Sheath Neoplasms/metabolism
  • Neural Crest/metabolism
  • Neural Crest/pathology
  • SOXE Transcription Factors/genetics
  • SOXE Transcription Factors/metabolism
  • Tumor Suppressor Protein p53/genetics*
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 27655644 Full text @ Oncotarget
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.