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p300 Serine 89: A Critical Signaling Integrator and Its Effects on Intestinal Homeostasis and Repair

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2021

Cancers (Basel). 2021 Mar 14;13(6):1288. doi: 10.3390/cancers13061288.

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

Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA. Department of Anatomic Pathology, Cleveland Clinic, Cleveland, OH 44195, USA. The Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan. Clinical Microbiome Service Center and Pathogen and Microbiome Division, Translational Genomics Research Institute, Flagstaff, AZ 86005, USA. Department of Pathology and Laboratory Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Department of Molecular and Cellular Endocrinology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA. Department of Clinical Proteomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan. Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.

Service type: Knock-in mice

Abstract

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.

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