p21/Zbtb18 repress the expression of cKit to regulate the self-renewal of hematopoietic stem cells.

IF 13.6 1区 生物学 Q1 CELL BIOLOGY Protein & Cell Pub Date : 2024-11-01 DOI:10.1093/procel/pwae022
Nini Wang, Shangda Yang, Yu Li, Fanglin Gou, Yanling Lv, Xiangnan Zhao, Yifei Wang, Chang Xu, Bin Zhou, Fang Dong, Zhenyu Ju, Tao Cheng, Hui Cheng
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Abstract

The maintenance of hematopoietic stem cells (HSCs) is a complex process involving numerous cell-extrinsic and -intrinsic regulators. The first member of the cyclin-dependent kinase family of inhibitors to be identified, p21, has been reported to perform a wide range of critical biological functions, including cell cycle regulation, transcription, differentiation, and so on. Given the previous inconsistent results regarding the functions of p21 in HSCs in a p21-knockout mouse model, we employed p21-tdTomato (tdT) mice to further elucidate its role in HSCs during homeostasis. The results showed that p21-tdT+ HSCs exhibited increased self-renewal capacity compared to p21-tdT- HSCs. Zbtb18, a transcriptional repressor, was upregulated in p21-tdT+ HSCs, and its knockdown significantly impaired the reconstitution capability of HSCs. Furthermore, p21 interacted with ZBTB18 to co-repress the expression of cKit in HSCs and thus regulated the self-renewal of HSCs. Our data provide novel insights into the physiological role and mechanisms of p21 in HSCs during homeostasis independent of its conventional role as a cell cycle inhibitor.

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p21/Zbtb18 抑制 cKit 的表达,从而调节造血干细胞的自我更新。
造血干细胞(HSCs)的维持是一个复杂的过程,涉及众多细胞内外调控因子。据报道,细胞周期蛋白依赖性激酶抑制剂家族的第一个成员p21具有广泛的关键生物学功能,包括细胞周期调控、转录、分化等。鉴于之前在p21基因敲除小鼠模型中关于p21在造血干细胞中功能的结果不一致,我们采用了p21-tdTomato(tdT)小鼠来进一步阐明其在造血干细胞稳态过程中的作用。结果显示,与 p21-tdT- HSCs 相比,p21-tdT+ HSCs 表现出更强的自我更新能力。转录抑制因子Zbtb18在p21-tdT+造血干细胞中上调,敲除Zbtb18会显著削弱造血干细胞的重建能力。此外,p21与ZBTB18相互作用,共同抑制造血干细胞中cKit的表达,从而调控造血干细胞的自我更新。我们的数据为了解 p21 在造血干细胞平衡过程中的生理作用和机制提供了新的视角,而不局限于其作为细胞周期抑制剂的传统作用。
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来源期刊
Protein & Cell
Protein & Cell CELL BIOLOGY-
CiteScore
24.00
自引率
0.90%
发文量
1029
审稿时长
6-12 weeks
期刊介绍: Protein & Cell is a monthly, peer-reviewed, open-access journal focusing on multidisciplinary aspects of biology and biomedicine, with a primary emphasis on protein and cell research. It publishes original research articles, reviews, and commentaries across various fields including biochemistry, biophysics, cell biology, genetics, immunology, microbiology, molecular biology, neuroscience, oncology, protein science, structural biology, and translational medicine. The journal also features content on research policies, funding trends in China, and serves as a platform for academic exchange among life science researchers.
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