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乳腺上皮细胞中NOTCH1转运和信号传导的新决定因素。

Novel determinants of NOTCH1 trafficking and signaling in breast epithelial cells.

作者信息

Kobia Francis M, Castro E Almeida Luis, Paganoni Alyssa Jj, Carminati Francesca, Andronache Adrian, Lavezzari Francesco, Wade Mark, Vaccari Thomas

机构信息

Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy

Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy.

出版信息

Life Sci Alliance. 2024 Dec 11;8(3). doi: 10.26508/lsa.202403122. Print 2025 Mar.

DOI:10.26508/lsa.202403122
PMID:39663000
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11633778/
Abstract

The evolutionarily conserved Notch signaling pathway controls cell-cell communication, enacting cell fate decisions during development and tissue homeostasis. Its dysregulation is associated with a wide range of diseases, including congenital disorders and cancers. Signaling outputs depend on maturation of Notch receptors and trafficking to the plasma membrane, endocytic uptake and sorting, lysosomal and proteasomal degradation, and ligand-dependent and independent proteolytic cleavages. We devised assays to follow quantitatively the trafficking and signaling of endogenous human NOTCH1 receptor in breast epithelial cells in culture. Based on such analyses, we executed a high-content screen of 2,749 human genes to identify new regulators of Notch that might be amenable to pharmacologic intervention. We uncovered 39 new NOTCH1 modulators for NOTCH1 trafficking and signaling. Among them, we find that and act as positive NOTCH1 regulators by promoting endocytic trafficking and NOTCH1 maturation in the Golgi apparatus, respectively, whereas serves as a negative regulator that can be modulated by pharmacologic inhibition. Our findings might be relevant in the search of new strategies to counteract pathologic Notch signaling.

摘要

进化上保守的Notch信号通路控制细胞间通讯，在发育和组织稳态过程中决定细胞命运。其失调与多种疾病相关，包括先天性疾病和癌症。信号输出取决于Notch受体的成熟、向质膜的运输、内吞摄取和分选、溶酶体和蛋白酶体降解以及配体依赖性和非依赖性蛋白水解切割。我们设计了实验来定量追踪培养的乳腺上皮细胞中内源性人类NOTCH1受体的运输和信号传导。基于这些分析，我们对2749个人类基因进行了高内涵筛选，以鉴定可能适用于药物干预的Notch新调节因子。我们发现了39个NOTCH1运输和信号传导的新调节因子。其中，我们发现 和 分别通过促进内吞运输和高尔基体中NOTCH1的成熟而作为NOTCH1的正向调节因子，而 作为负向调节因子，可通过药物抑制进行调节。我们的发现可能与寻找对抗病理性Notch信号传导的新策略相关。

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本文引用的文献

1
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Cell Death Dis. 2023 Jan 27;14(1):63. doi: 10.1038/s41419-023-05593-7.
2
Transcriptomics indicate nuclear division and cell adhesion not recapitulated in MCF7 and MCF10A compared to luminal A breast tumours.转录组学表明，与腔 A 型乳腺癌相比，MCF7 和 MCF10A 中未再现核分裂和细胞黏附。
Sci Rep. 2022 Dec 3;12(1):20902. doi: 10.1038/s41598-022-24511-z.
3
The MASTL/PP2A cell cycle kinase-phosphatase module restrains PI3K-Akt activity in an mTORC1-dependent manner.
MASTL/PP2A 细胞周期激酶-磷酸酶模块以 mTORC1 依赖的方式抑制 PI3K-Akt 活性。
EMBO J. 2023 Jan 16;42(2):e110833. doi: 10.15252/embj.2022110833. Epub 2022 Nov 10.
4
Low TINAGL1 expression is a marker for poor prognosis in breast cancer.TINAGL1 低表达是乳腺癌预后不良的标志物。
J Cancer Res Clin Oncol. 2023 Jul;149(8):4771-4782. doi: 10.1007/s00432-022-04394-3. Epub 2022 Oct 14.
5
A multi-omic analysis of MCF10A cells provides a resource for integrative assessment of ligand-mediated molecular and phenotypic responses.多组学分析 MCF10A 细胞为整合评估配体介导的分子和表型反应提供了资源。
Commun Biol. 2022 Oct 7;5(1):1066. doi: 10.1038/s42003-022-03975-9.
6
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J Biol Chem. 2022 Oct;298(10):102475. doi: 10.1016/j.jbc.2022.102475. Epub 2022 Sep 9.
7
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EMBO J. 2022 Jul 18;41(14):e110155. doi: 10.15252/embj.2021110155. Epub 2022 May 25.
8
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Nat Commun. 2022 Mar 17;13(1):1421. doi: 10.1038/s41467-022-28937-x.
9
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Sci Rep. 2022 Jan 31;12(1):1655. doi: 10.1038/s41598-022-05666-1.
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Clin Transl Med. 2021 Nov;11(11):e578. doi: 10.1002/ctm2.578.