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ZFIN ID: ZDB-PUB-151119-7
The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration
Hesse, R.G., Kouklis, G.K., Ahituv, N., Pomerantz, J.H.
Date: 2015
Source: eLIFE 4: (Journal)
Registered Authors: Ahituv, Nadav
Keywords: ARF, chromosomes, developmental biology, evolution, genes, human, regeneration, stem cells, tumor suppressors, zebrafish
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • E2F Transcription Factors/metabolism
  • Humans
  • Promoter Regions, Genetic
  • Protein Binding
  • Regeneration*
  • Tumor Suppressor Protein p14ARF/metabolism*
  • Tumor Suppressor Protein p53/metabolism
  • Zebrafish
PubMed: 26575287 Full text @ Elife
The control of proliferation and differentiation by tumor suppressor genes suggests that evolution of divergent tumor suppressor repertoires could influence species' regenerative capacity. To directly test that premise, we humanized the zebrafish p53 pathway by introducing regulatory and coding sequences of the human tumor suppressor ARF into the zebrafish genome. ARF was dormant during development, in uninjured adult fins, and during wound healing, but was highly expressed in the blastema during epimorphic fin regeneration after amputation. Regenerative, but not developmental signals resulted in binding of zebrafish E2f to the human ARF promoter and activated conserved ARF-dependent Tp53 functions. The context-dependent activation of ARF did not affect growth and development but inhibited regeneration, an unexpected distinct tumor suppressor response to regenerative versus developmental environments. The antagonistic pleiotropic characteristics of ARF as both tumor and regeneration suppressor imply that inducing epimorphic regeneration clinically would require modulation of ARF -p53 axis activation.