P300 serine 89: A critical signaling integrator and its effects on intestinal homeostasis and repair

Keane K.Y. Lai, Xiaohui Hu, Keisuke Chosa, Cu Nguyen, David P. Lin, Keith K. Lai, Nobuo Kato, Yusuke Higuchi, Sarah K. Highlander, Elizabeth Melendez, Yoshihiro Eriguchi, Patrick T. Fueger, Andre J. Ouellette, Nyam Osor Chimge, Masaya Ono, Michael Kahn

研究成果: Contribution to journalArticle査読

抄録

Differential usage of Kat3 coactivators, CBP and p300, by β-catenin is a fundamental regulatory mechanism in stem cell maintenance and initiation of differentiation and repair. Based upon our earlier pharmacologic studies, p300 serine 89 (S89) is critical for controlling differential coactivator usage by β-catenin via post-translational phosphorylation in stem/progenitor populations, and appears to be a target for a number of kinase cascades. To further investigate mechanisms of signal integration effected by this domain, we generated p300 S89A knock-in mice. We show that S89A mice are extremely sensitive to intestinal insult resulting in colitis, which is known to significantly increase the risk of developing colorectal cancer. We demonstrate cell intrinsic differences, and microbiome compositional differences and differential immune responses, in intestine of S89A versus wild type mice. Genomic and proteomic analyses reveal pathway differences, including lipid metabolism, oxidative stress response, mitochondrial function and oxidative phosphorylation. The diverse effects on fundamental processes including epithelial differentiation, metabolism, immune response and microbiome colonization, all brought about by a single amino acid modification S89A, highlights the critical role of this region in p300 as a signaling nexus and the rationale for conservation of this residue and surrounding region for hundreds of million years of vertebrate evolution.

本文言語英語
論文番号1288
ページ(範囲)1-22
ページ数22
ジャーナルCancers
13
6
DOI
出版ステータス出版済み - 3 2 2021
外部発表はい

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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