title: The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration.
abstract: 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.
authors.affiliation: Department of Surgery, Division of Plastic Surgery, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, United States.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Hesse
authors.affiliation: Department of Surgery, Division of Plastic Surgery, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, United States.
authors.forename: Gayle K
authors.initials: GK
authors.lastname: Kouklis
authors.affiliation: Department of Bioengineering and Therapeutic Sciences and Institute for Human Genetics, University of California, San Francisco, San Francisco, United States.
authors.forename: Nadav
authors.initials: N
authors.lastname: Ahituv
authors.affiliation: Departments of Surgery and Orofacial Sciences, Division of Plastic Surgery, Program in Craniofacial Biology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Pomerantz
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D050684:E2F Transcription Factors / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012038:Regeneration; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015027:Zebrafish
chemical_list: D050684:E2F Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53
keywords: ARF; chromosomes; developmental biology; evolution; genes; human; regeneration; stem cells; tumor suppressors; zebrafish