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p21/Zbtb18 通过抑制 cKit 的表达来调控造血干细胞的自我更新。

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

机构信息

State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.

CAMS Center for Stem Cell Medicine, PUMC Department of Stem Cell and Regenerative Medicine, Tianjin 300020, China.

出版信息

Protein Cell. 2024 Nov 1;15(11):840-857. doi: 10.1093/procel/pwae022.

DOI:10.1093/procel/pwae022
PMID:38721703
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11528518/
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.

摘要

造血干细胞（HSCs）的维持是一个复杂的过程，涉及许多细胞外和细胞内的调节因子。p21 是第一个被鉴定的细胞周期蛋白依赖性激酶家族抑制剂，据报道，它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 敲除小鼠模型中 p21 在 HSCs 中的功能存在不一致的结果，我们使用了 p21-tdTomato（tdT）小鼠来进一步阐明其在 HSCs 稳态中的作用。结果表明，与 p21-tdT- HSCs 相比，p21-tdT+ HSCs 表现出更高的自我更新能力。转录抑制因子 Zbtb18 在 p21-tdT+ HSCs 中上调，其敲低显著损害了 HSCs 的重建能力。此外，p21 与 ZBTB18 相互作用，共同抑制 HSCs 中 cKit 的表达，从而调节 HSCs 的自我更新。我们的数据提供了新的见解，即 p21 在 HSCs 稳态中的生理作用和机制独立于其作为细胞周期抑制剂的传统作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/becaf38d9330/pwae022_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/8c302a284494/pwae022_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/9d08fd45d4d5/pwae022_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/f20a0d9783b6/pwae022_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/70f2c5c0445c/pwae022_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/50ffbbc278ef/pwae022_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/e0f117f06f5a/pwae022_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/becaf38d9330/pwae022_fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/8c302a284494/pwae022_fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/9d08fd45d4d5/pwae022_fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/f20a0d9783b6/pwae022_fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/70f2c5c0445c/pwae022_fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/50ffbbc278ef/pwae022_fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/e0f117f06f5a/pwae022_fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e80a/11528518/becaf38d9330/pwae022_fig7.jpg

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Low c-Kit expression identifies primitive, therapy-resistant CML stem cells.低 c-Kit 表达鉴定出原始的、治疗抵抗的 CML 干细胞。
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CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication.p21 在 DNA 复制中的 CDK 非依赖性和 PCNA 依赖性功能。
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