Hesse Robert G, Kouklis Gayle K, Ahituv Nadav, Pomerantz Jason H
Department of Surgery, Division of Plastic Surgery, Program in Craniofacial Biology, University of California, San Francisco, San Francisco, United States.
Department of Bioengineering and Therapeutic Sciences and Institute for Human Genetics, University of California, San Francisco, San Francisco, United States.
Elife. 2015 Nov 17;4:e07702. doi: 10.7554/eLife.07702.
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.
肿瘤抑制基因对细胞增殖和分化的控制表明，不同肿瘤抑制基因库的进化可能会影响物种的再生能力。为了直接验证这一前提，我们通过将人类肿瘤抑制因子ARF的调控序列和编码序列引入斑马鱼基因组，对斑马鱼的p53信号通路进行了人源化改造。在发育过程中、未受伤的成年鱼鳍以及伤口愈合期间，ARF处于休眠状态，但在截肢后的形态再生鳍芽中高度表达。再生信号而非发育信号导致斑马鱼E2f与人类ARF启动子结合，并激活保守的ARF依赖的Tp53功能。ARF的上下文依赖性激活不影响生长和发育，但抑制再生，这是一种对再生环境与发育环境的意外的独特肿瘤抑制反应。ARF作为肿瘤和再生抑制因子的拮抗多效性特征意味着，临床上诱导形态再生将需要调节ARF-p53轴的激活。
