• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

内吞蛋白 intersectin1-S 穿梭进入细胞核，抑制乳腺癌中的 DNA 复制。

Endocytic protein intersectin1-S shuttles into nucleus to suppress the DNA replication in breast cancer.

机构信息

Department of Tumor Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China.

Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

出版信息

Cell Death Dis. 2021 Oct 8;12(10):922. doi: 10.1038/s41419-021-04218-1.

DOI:10.1038/s41419-021-04218-1
PMID:34625530
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8501101/
Abstract

Breast cancer is the most common type of cancer worldwide. However, the well-known molecular biomarkers are not enough to meet the needs of precision medicine. In search for novel targets in this regard, we reported ITSN1 (intersectin1) as one of the candidates through mRNA microarray analysis. In the present study, we reported that endocytic protein ITSN1-S exists not only in the cytoplasm but also in nuclei of breast cancer cells. ITSN1-S' functional nuclear localization signal is within its residues 306-312. Its nuclear export signal (NES) resides within its SH3 domains. We also found, the interaction between the CC domain of nuclear ITSN1-S and the NT domain of nuclear DNA helicase II (NDH II) directly suppressed the DNA replication and nascent DNA synthesis by inhibiting the R-loops resolution in breast cancer cells. Furthermore, the interaction between the EH domains of cytoplasmic ITSN1-S and PI3KC2α inhibit cell migration and invasion by inactivating the PI3KC2α-AKT pathway. Our results were confirmed in both ITSN1 gene knockout cells and in vivo assays. Finally, our clinical data showed a potential application of the combined consideration of the cytoplasmic and nuclear ITSN1-S as an independent prognosis factor. In conclusion, our study revealed ITSN1-S' novel positioning in the nuclei of breast cancer cells, its function in suppressing DNA replication, and its potential application in improved breast cancer prognosis.

摘要

乳腺癌是全球最常见的癌症类型。然而，众所周知的分子生物标志物不足以满足精准医学的需求。在寻找这方面的新靶点时，我们通过 mRNA 微阵列分析报告了 ITSN1（ intersectin1）是候选物之一。在本研究中，我们报告了内体蛋白 ITSN1-S 不仅存在于细胞质中，也存在于乳腺癌细胞的细胞核中。ITSN1-S 的功能性核定位信号位于其残基 306-312 内。其核输出信号（NES）位于其 SH3 结构域内。我们还发现，核 ITSN1-S 的 CC 结构域与核 DNA 解旋酶 II（NDH II）的 NT 结构域之间的相互作用直接通过抑制乳腺癌细胞中的 R 环解旋来抑制 DNA 复制和新生 DNA 合成。此外，细胞质 ITSN1-S 的 EH 结构域与 PI3KC2α 的相互作用通过使 PI3KC2α-AKT 途径失活来抑制细胞迁移和侵袭。我们的结果在 ITSN1 基因敲除细胞和体内实验中得到了证实。最后，我们的临床数据表明，同时考虑细胞质和核 ITSN1-S 作为独立的预后因素具有潜在的应用价值。总之，我们的研究揭示了 ITSN1-S 在乳腺癌细胞核中的新定位、其抑制 DNA 复制的功能以及其在改善乳腺癌预后方面的潜在应用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/1285850c4b64/41419_2021_4218_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/27ed8d57d354/41419_2021_4218_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/d7df7493c560/41419_2021_4218_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/cbfaf8d04793/41419_2021_4218_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/5e252c0f720b/41419_2021_4218_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/b3bfdf5e7bea/41419_2021_4218_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/bf01072727c9/41419_2021_4218_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/ce14d96e1f43/41419_2021_4218_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/1285850c4b64/41419_2021_4218_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/27ed8d57d354/41419_2021_4218_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/d7df7493c560/41419_2021_4218_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/cbfaf8d04793/41419_2021_4218_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/5e252c0f720b/41419_2021_4218_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/b3bfdf5e7bea/41419_2021_4218_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/bf01072727c9/41419_2021_4218_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/ce14d96e1f43/41419_2021_4218_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4438/8501101/1285850c4b64/41419_2021_4218_Fig8_HTML.jpg

相似文献

1
Endocytic protein intersectin1-S shuttles into nucleus to suppress the DNA replication in breast cancer.内吞蛋白 intersectin1-S 穿梭进入细胞核，抑制乳腺癌中的 DNA 复制。
Cell Death Dis. 2021 Oct 8;12(10):922. doi: 10.1038/s41419-021-04218-1.
2
Intersectin goes nuclear: secret life of an endocytic protein.衔接蛋白入核：内吞蛋白的隐秘生活。
Biochem J. 2018 Apr 27;475(8):1455-1472. doi: 10.1042/BCJ20170897.
3
Intersectin1-S, a multidomain adapter protein, is essential for malignant glioma proliferation.衔接蛋白 1-S，一种多功能衔接蛋白，对恶性神经胶质瘤的增殖至关重要。
Glia. 2015 Sep;63(9):1595-605. doi: 10.1002/glia.22830. Epub 2015 Apr 2.
4
Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression.剪接变异体 intersectin1-L 和 intersectin1-S 在胶质瘤进展中发挥相反的作用。
Cell Death Dis. 2019 Jun 3;10(6):431. doi: 10.1038/s41419-019-1668-0.
5
Identification and characterization of a novel mammalian isoform of the endocytic adaptor ITSN1.鉴定和表征新型哺乳动物内吞衔接蛋白 ITSN1 的同工型。
Gene. 2011 Oct 10;485(2):120-9. doi: 10.1016/j.gene.2011.06.021. Epub 2011 Jun 25.
6
Structural diversity and differential expression of novel human intersectin 1 isoforms.新型人 intersectin 1 异构体的结构多样性和差异表达。
Mol Biol Rep. 2010 Jul;37(6):2789-96. doi: 10.1007/s11033-009-9824-8. Epub 2009 Sep 24.
7
Intersectin1-s is involved in migration and invasion of human glioma cells.衔接蛋白 1-s 参与人脑胶质瘤细胞的迁移和侵袭。
J Neurosci Res. 2011 Jul;89(7):1079-90. doi: 10.1002/jnr.22616. Epub 2011 Apr 18.
8
ITSN1 regulates SAM68 solubility through SH3 domain interactions with SAM68 proline-rich motifs.ITSN1 通过与 SAM68 富含脯氨酸的基序的 SH3 结构域相互作用来调节 SAM68 的可溶性。
Cell Mol Life Sci. 2021 Feb;78(4):1745-1763. doi: 10.1007/s00018-020-03610-y. Epub 2020 Aug 11.
9
Microexon-based regulation of ITSN1 and Src SH3 domains specificity relies on introduction of charged amino acids into the interaction interface.基于微外显子的 ITSN1 和 Src SH3 结构域特异性调节依赖于将带电荷的氨基酸引入相互作用界面。
Biochem Biophys Res Commun. 2010 Aug 20;399(2):307-12. doi: 10.1016/j.bbrc.2010.07.080. Epub 2010 Jul 24.
10
The LMP2A protein of Epstein-Barr virus regulates phosphorylation of ITSN1 and Shb adaptors by tyrosine kinases.EB 病毒的 LMP2A 蛋白通过酪氨酸激酶调节 ITSN1 和 Shb 接头蛋白的磷酸化。
Cell Signal. 2013 Jan;25(1):33-40. doi: 10.1016/j.cellsig.2012.09.011. Epub 2012 Sep 10.

引用本文的文献

1
Novel metastasis suppressor PI3KC2β is mediated by mTORC1 signalling in breast cancer.新型转移抑制因子PI3KC2β在乳腺癌中由mTORC1信号传导介导。
Mol Cancer Res. 2025 May 13. doi: 10.1158/1541-7786.MCR-24-1045.
2
Comprehensive evaluation of breast cancer immunotherapy and tumor microenvironment characterization based on interleukin genes-related risk model.基于白细胞介素基因相关风险模型的乳腺癌免疫治疗综合评估及肿瘤微环境特征分析
Sci Rep. 2022 Nov 28;12(1):20524. doi: 10.1038/s41598-022-25059-8.

本文引用的文献

1
Breast Cancer Predisposition Genes and Synthetic Lethality.乳腺癌易感基因与合成致死性
Int J Mol Sci. 2021 May 25;22(11):5614. doi: 10.3390/ijms22115614.
2
Recognition of RNA by the S9.6 antibody creates pervasive artifacts when imaging RNA:DNA hybrids.S9.6 抗体识别 RNA：DNA 杂交体时会产生普遍的假象。
J Cell Biol. 2021 Jun 7;220(6). doi: 10.1083/jcb.202004079.
3
Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries.《全球癌症统计数据 2020：全球 185 个国家和地区 36 种癌症的发病率和死亡率估计》。
CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.
4
Cancer burden in China: trends, risk factors and prevention.中国癌症负担：趋势、风险因素与预防。
Cancer Biol Med. 2020 Nov 15;17(4):879-895. doi: 10.20892/j.issn.2095-3941.2020.0387. Epub 2020 Dec 15.
5
DNA damage repair functions and targeted treatment in breast cancer.乳腺癌中的 DNA 损伤修复功能与靶向治疗。
Breast Cancer. 2020 May;27(3):355-362. doi: 10.1007/s12282-019-01038-2. Epub 2020 Jan 2.
6
Alternative splicing-derived intersectin1-L and intersectin1-S exert opposite function in glioma progression.剪接变异体 intersectin1-L 和 intersectin1-S 在胶质瘤进展中发挥相反的作用。
Cell Death Dis. 2019 Jun 3;10(6):431. doi: 10.1038/s41419-019-1668-0.
7
PI3K isoforms in cell signalling and vesicle trafficking.PI3K 异构体在细胞信号转导和囊泡运输中的作用。
Nat Rev Mol Cell Biol. 2019 Sep;20(9):515-534. doi: 10.1038/s41580-019-0129-z.
8
Human mitochondrial degradosome prevents harmful mitochondrial R loops and mitochondrial genome instability.人线粒体降解体防止有害的线粒体 R 环和线粒体基因组不稳定性。
Proc Natl Acad Sci U S A. 2018 Oct 23;115(43):11024-11029. doi: 10.1073/pnas.1807258115. Epub 2018 Oct 9.
9
The Rules and Functions of Nucleocytoplasmic Shuttling Proteins.核质穿梭蛋白的规则和功能。
Int J Mol Sci. 2018 May 12;19(5):1445. doi: 10.3390/ijms19051445.
10
RNA/DNA Hybrid Interactome Identifies DXH9 as a Molecular Player in Transcriptional Termination and R-Loop-Associated DNA Damage.RNA/DNA 杂交互作组鉴定 DXH9 为转录终止和 R 环相关 DNA 损伤中的分子参与者。
Cell Rep. 2018 May 8;23(6):1891-1905. doi: 10.1016/j.celrep.2018.04.025.