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在表皮干细胞中 CDK1 和 FOXM1 之间正反馈环的生化特征。

Biochemical characterization of the feedforward loop between CDK1 and FOXM1 in epidermal stem cells.

机构信息

Centre for Regenerative Medicine "Stefano Ferrari", Department of Life Science, University of Modena and Reggio Emilia, Via Glauco Gottardi 100, Modena, Italy.

Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy.

出版信息

Biol Direct. 2024 Oct 13;19(1):91. doi: 10.1186/s13062-024-00540-8.

DOI:10.1186/s13062-024-00540-8
PMID:39396994
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11472434/
Abstract

The complex network governing self-renewal in epidermal stem cells (EPSCs) is only partially defined. FOXM1 is one of the main players in this network, but the upstream signals regulating its activity remain to be elucidated. In this study, we identify cyclin-dependent kinase 1 (CDK1) as the principal kinase controlling FOXM1 activity in human primary keratinocytes. Mass spectrometry identified CDK1 as a key hub in a stem cell-associated protein network, showing its upregulation and interaction with essential self renewal-related markers. CDK1 phosphorylates FOXM1 at specific residues, stabilizing the protein and enhancing its nuclear localization and transcriptional activity, promoting self-renewal. Additionally, FOXM1 binds to the CDK1 promoter, inducing its expression.We identify the CDK1-FOXM1 feedforward loop as a critical axis sustaining EPSCs during in vitro cultivation. Understanding the upstream regulators of FOXM1 activity offers new insights into the biochemical mechanisms underlying self-renewal and differentiation in human primary keratinocytes.

摘要

表皮干细胞（EPSCs）自我更新的复杂网络仅部分定义。FOXM1 是该网络中的主要参与者之一，但调节其活性的上游信号仍有待阐明。在这项研究中，我们确定细胞周期蛋白依赖性激酶 1（CDK1）是控制人原代角质形成细胞中 FOXM1 活性的主要激酶。质谱分析将 CDK1 鉴定为干细胞相关蛋白网络中的关键枢纽，显示其上调并与重要的自我更新相关标志物相互作用。CDK1 在特定残基上磷酸化 FOXM1，稳定蛋白质并增强其核定位和转录活性，促进自我更新。此外，FOXM1 结合 CDK1 启动子，诱导其表达。我们确定 CDK1-FOXM1 正反馈回路是体外培养过程中维持 EPSCs 的关键轴。了解 FOXM1 活性的上游调节剂为人类原代角质形成细胞中的自我更新和分化的生化机制提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c48/11472434/2d1ec42c8c67/13062_2024_540_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c48/11472434/2d9e2b62ddb4/13062_2024_540_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c48/11472434/8de6f500b19f/13062_2024_540_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c48/11472434/2d1ec42c8c67/13062_2024_540_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c48/11472434/2d9e2b62ddb4/13062_2024_540_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c48/11472434/8de6f500b19f/13062_2024_540_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7c48/11472434/2d1ec42c8c67/13062_2024_540_Fig3_HTML.jpg

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