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PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis.

Developmental cell | Mar 12, 2018

The underlying mechanisms of how self-renewing cells are controlled in regenerating tissues and cancer remain ambiguous. PCNA-associated factor (PAF) modulates DNA repair via PCNA. Also, PAF hyperactivates Wnt/β-catenin signaling independently of PCNA interaction. We found that PAF is expressed in intestinal stem and progenitor cells (ISCs and IPCs) and markedly upregulated during intestinal regeneration and tumorigenesis. Whereas PAF is dispensable for intestinal homeostasis, upon radiation injury, genetic ablation of PAF impairs intestinal regeneration along with the severe loss of ISCs and Myc expression. Mechanistically, PAF conditionally occupies and transactivates the c-Myc promoter, which induces the expansion of ISCs/IPCs during intestinal regeneration. In mouse models, PAF knockout inhibits Apc inactivation-driven intestinal tumorigenesis with reduced tumor cell stemness and suppressed Wnt/β-catenin signaling activity, supported by transcriptome profiling. Collectively, our results unveil that the PAF-Myc signaling axis is indispensable for intestinal regeneration and tumorigenesis by positively regulating self-renewing cells.

Pubmed ID: 29533773 RIS Download

Mesh terms: Animals | Carcinogenesis | Carrier Proteins | Cell Proliferation | Female | Gene Expression Profiling | Homeostasis | Intestines | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Neoplastic Stem Cells | Pluripotent Stem Cells | Proto-Oncogene Proteins c-myc | Regeneration | Wnt Signaling Pathway

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Associated grants

  • Agency: NCI NIH HHS, Id: P30 CA016672
  • Agency: NCI NIH HHS, Id: P50 CA098258
  • Agency: NCI NIH HHS, Id: R01 CA193297

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