Genetic inhibition of autophagy promotes p53 loss-ofheterozygosity and tumorigenesis

Eunmyong Lee, Yongjie Wei, Zhongju Zou, Kathryn Tucker, Dinesh Rakheja, Beth Levine, James F Amatruda

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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 dominantnegative atg5K130R increased tumor incidence and decreased tumor latency compared to non-transgenic heterozygous tp53 mutant controls. In a tp53-deficient background, Tg(mitfa:atg5K130R) mutants developed 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.

Original languageEnglish (US)
Pages (from-to)67919-67933
Number of pages15
JournalOncotarget
Volume7
Issue number42
DOIs
StatePublished - 2016

Keywords

  • Autophagy
  • Loss-of-heterozygosity
  • MPNST
  • P53
  • Zebrafish

ASJC Scopus subject areas

  • Oncology

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