PAF-Myc-Controlled Cell Stemness Is Required for Intestinal Regeneration and Tumorigenesis
| Autor: | Han Na Suh, Sung Ho Lee, Bo Xia, Jie Zhang, Kaifu Chen, Moon Jong Kim, Sohee Jun, Esther M. Lien, Jae Il Park |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Pluripotent Stem Cells 0301 basic medicine Carcinogenesis Cell Biology medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology Proto-Oncogene Proteins c-myc Mice 03 medical and health sciences Downregulation and upregulation Cancer stem cell medicine Animals Homeostasis Regeneration Intestinal Mucosa Progenitor cell Wnt Signaling Pathway Molecular Biology Cell Proliferation Mice Knockout Gene Expression Profiling Regeneration (biology) Wnt signaling pathway Cell Biology Cell biology Proliferating cell nuclear antigen Intestines Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Neoplastic Stem Cells biology.protein Female lipids (amino acids peptides and proteins) Carrier Proteins Developmental Biology |
| Zdroj: | Developmental Cell. 44:582-596.e4 |
| ISSN: | 1534-5807 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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