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<p>CREB-binding protein (CBP) is a transcriptional coactivator, and we reported its phosphorylation regulates cell fate. Impaired CBP phosphorylation alters its binding preference for p53 in <i>CBP</i><sup><i>AA</i></sup> mice, leading to distal colonic abnormalities. These changes are accompanied by reduced expression of versican, an extracellular matrix component that supports the intestinal stem cell niche, leading to impaired intestinal epithelial cell (IEC) proliferation and organoid formation. Deleting p53 in the IECs of <i>CBP</i><sup><i>AA</i></sup> mice (<i>CBP</i><sup><i>AA</i></sup><i>p53</i><sup><i>ΔIEC</i></sup>) restores versican expression and reverses the colonic phenotype. Versican replenishment and phosphomimetic CBP mutants rescue versican expression and IEC stemness in <i>CBP</i><sup><i>AA</i></sup> organoids. Importantly, colonic tissues from ulcerative colitis patients exhibit impaired CBP phosphorylation, increased CBP–p53 binding, decreased versican expression and IEC proliferation, highlighting the clinical relevance of this phenomenon. In this work, we demonstrate CBP phosphorylation safeguards intestinal homeostasis by maintaining the stem cell niche through versican, highlighting versican as a potential therapeutic target for inflammatory bowel disease.</p>

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CBP phosphorylation maintains intestinal homeostasis by supporting the stem cell niche through versican

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月28日

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  • Yi-Ting Lin,
  • Chi Liu,
  • Yu-Hua Hsu,
  • Shi-Chuen Miaw,
  • Ming-Shiang Wu,
  • Ching-Chow Chen

摘要

CREB-binding protein (CBP) is a transcriptional coactivator, and we reported its phosphorylation regulates cell fate. Impaired CBP phosphorylation alters its binding preference for p53 in CBPAA mice, leading to distal colonic abnormalities. These changes are accompanied by reduced expression of versican, an extracellular matrix component that supports the intestinal stem cell niche, leading to impaired intestinal epithelial cell (IEC) proliferation and organoid formation. Deleting p53 in the IECs of CBPAA mice (CBPAAp53ΔIEC) restores versican expression and reverses the colonic phenotype. Versican replenishment and phosphomimetic CBP mutants rescue versican expression and IEC stemness in CBPAA organoids. Importantly, colonic tissues from ulcerative colitis patients exhibit impaired CBP phosphorylation, increased CBP–p53 binding, decreased versican expression and IEC proliferation, highlighting the clinical relevance of this phenomenon. In this work, we demonstrate CBP phosphorylation safeguards intestinal homeostasis by maintaining the stem cell niche through versican, highlighting versican as a potential therapeutic target for inflammatory bowel disease.