Suppr超能文献

磷酸酶 CTDSPL2 在有丝分裂中被磷酸化,是抑制胰腺癌肿瘤生长和运动的靶点。

The phosphatase CTDSPL2 is phosphorylated in mitosis and a target for restraining tumor growth and motility in pancreatic cancer.

机构信息

Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.

Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE, 68583, USA.

出版信息

Cancer Lett. 2022 Feb 1;526:53-65. doi: 10.1016/j.canlet.2021.11.018. Epub 2021 Nov 20.

Abstract

Carboxy-terminal domain (CTD) small phosphatase like 2 (CTDSPL2), also known as SCP4 or HSPC129, is a new member of the small CTD phosphatase (SCP) family and its role in cancers remains unclear. Here, we used a Phos-tag technique to screen a series of phosphatases and identified CTDSPL2 as a mitotic regulator. We demonstrated that CTDSPL2 was phosphorylated at T86, S104, and S134 by cyclin-dependent kinase 1 (CDK1) in mitosis. Depletion of CTDSPL2 led to mitotic defects and prolonged mitosis. Resultantly, CTDSPL2 deletion restrained proliferation, migration, and invasion in pancreatic cancer cells. We further confirmed the dominant negative effects of a phosphorylation-deficient mutant form of CTDSPL2, implying the biological significance of CTDSPL2 mitotic phosphorylation. Moreover, RT cell cycle array analysis revealed p21 and p27 as downstream regulators of CTDSPL2, and inhibition of p21 and/or p27 partially rescued the phenotype in CTDSPL2-deficient cell lines. Importantly, both CTDSPL2 depletion and phosphorylation-deficient mutant CTDSPL2 hindered tumor growth in xenograft models. Together, our findings for the first time highlight the novel role of CTDSPL2 in regulating cell mitosis, proliferation and motility in pancreatic cancer and point out the implications of CTDSPL2 in regulating two critical cell cycle participants (p21 and p27), providing an alternative molecular target for pancreatic cancer treatment.

摘要

羧基末端结构域(CTD)小磷酸酶样 2(CTDSPL2),也称为 SCP4 或 HSPC129,是小 CTD 磷酸酶(SCP)家族的新成员,其在癌症中的作用尚不清楚。在这里,我们使用 Phos-tag 技术筛选了一系列磷酸酶,并鉴定 CTDSPL2 为有丝分裂调节剂。我们证明 CTDSPL2 在有丝分裂中被周期蛋白依赖性激酶 1(CDK1)磷酸化在 T86、S104 和 S134 位。CTDSPL2 缺失导致有丝分裂缺陷和有丝分裂延长。结果,CTDSPL2 缺失抑制了胰腺癌细胞的增殖、迁移和侵袭。我们进一步证实了 CTDSPL2 磷酸化缺陷突变形式的显性负效应,暗示了 CTDSPL2 有丝分裂磷酸化的生物学意义。此外,RT 细胞周期阵列分析显示 p21 和 p27 是 CTDSPL2 的下游调节因子,抑制 p21 和/或 p27 部分挽救了 CTDSPL2 缺失细胞系的表型。重要的是,CTDSPL2 缺失和磷酸化缺陷突变体 CTDSPL2 均能抑制异种移植模型中的肿瘤生长。总之,我们的研究结果首次强调了 CTDSPL2 在调节胰腺癌细胞有丝分裂、增殖和运动中的新作用,并指出了 CTDSPL2 在调节两个关键细胞周期参与者(p21 和 p27)中的意义,为胰腺癌治疗提供了替代的分子靶标。

相似文献

10
PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells.PCTAIRE1使p27磷酸化并调节癌细胞的有丝分裂。
Cancer Res. 2014 Oct 15;74(20):5795-807. doi: 10.1158/0008-5472.CAN-14-0872. Epub 2014 Sep 9.

引用本文的文献

2
A Transcriptomic Signature of Depressive Symptoms in Late Life.晚年抑郁症状的转录组特征
Biol Psychiatry Glob Open Sci. 2025 Jan 9;5(3):100448. doi: 10.1016/j.bpsgos.2025.100448. eCollection 2025 May.
7
DNA methylation in necrotizing enterocolitis.坏死性小肠结肠炎中的 DNA 甲基化。
Expert Rev Mol Med. 2024 Apr 1;26:e16. doi: 10.1017/erm.2024.16.

本文引用的文献

2
Targeting cell-cycle machinery in cancer.针对癌症中的细胞周期机制。
Cancer Cell. 2021 Jun 14;39(6):759-778. doi: 10.1016/j.ccell.2021.03.010. Epub 2021 Apr 22.
3
Cancer Statistics, 2021.癌症统计数据,2021.
CA Cancer J Clin. 2021 Jan;71(1):7-33. doi: 10.3322/caac.21654. Epub 2021 Jan 12.
4
Mitotic Poisons in Research and Medicine.有丝分裂毒物在研究和医学中的应用。
Molecules. 2020 Oct 12;25(20):4632. doi: 10.3390/molecules25204632.
6
Mechanisms of Sensitivity and Resistance to CDK4/6 Inhibition.CDK4/6 抑制敏感性和耐药性的机制。
Cancer Cell. 2020 Apr 13;37(4):514-529. doi: 10.1016/j.ccell.2020.03.010.
8
Hematological malignancies and molecular targeting therapy.血液系统恶性肿瘤与分子靶向治疗。
Eur J Pharmacol. 2019 Nov 5;862:172641. doi: 10.1016/j.ejphar.2019.172641. Epub 2019 Sep 4.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验