The human ARF tumor suppressor senses blastema activity and suppresses epimorphic tissue regeneration

Area of Science:

• Developmental Biology
• Cancer Biology
• Regenerative Medicine

Background:

• Tumor suppressor genes regulate cell proliferation and differentiation, potentially influencing species' regenerative capacities.
• Divergent tumor suppressor repertoires may impact regenerative potential across species.

Purpose of the Study:

• To investigate if tumor suppressor genes influence regenerative capacity.
• To test the hypothesis that divergent tumor suppressor repertoires affect species' regenerative capacity by humanizing the zebrafish p53 pathway with human ARF.

Main Methods:

• Humanized the zebrafish p53 pathway by introducing human ARF regulatory and coding sequences into the zebrafish genome.
• Assessed ARF expression during development, in uninjured fins, wound healing, and epimorphic fin regeneration.
• Analyzed zebrafish E2f binding to the human ARF promoter under regenerative and developmental signals.

Main Results:

• Human ARF was dormant during development, in uninjured adult fins, and during wound healing.
• ARF was highly expressed in the blastema during epimorphic fin regeneration.
• Regenerative signals, but not developmental signals, activated human ARF via zebrafish E2f, engaging conserved ARF-dependent Tp53 functions.
• Context-dependent ARF activation inhibited regeneration but not growth and development.

Conclusions:

• ARF exhibits antagonistic pleiotropy, acting as both a tumor suppressor and a regeneration suppressor.
• The distinct tumor suppressor response to regenerative versus developmental environments highlights context-dependent pathway activation.
• Clinical induction of epimorphic regeneration may necessitate modulation of the ARF-p53 axis.