转化生长因子-β通过蛋白磷酸酶2A抑制p70 S6激酶，从而诱导G(1)期阻滞。
TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest.
作者信息
Petritsch C, Beug H, Balmain A, Oft M
机构信息
IMP, Research Institute for Molecular Pathology, A-1030 Vienna, Austria.
出版信息
Genes Dev. 2000 Dec 15;14(24):3093-101. doi: 10.1101/gad.854200.
Abstract
On TGF-beta binding, the TGF-beta receptor directly phosphorylates and activates the transcription factors Smad2/3, leading to G(1) arrest. Here, we present evidence for a second, parallel, TGF-beta-dependent pathway for cell cycle arrest, achieved via inhibition of p70(s6k). TGF-beta induces association of its receptor with protein phosphatase-2A (PP2A)-Balpha. Concomitantly, three PP2A-subunits, Balpha, Abeta, and Calpha, associate with p70(s6k), leading to its dephosphorylation and inactivation. Although either pathway is sufficient to induce G(1) arrest, abrogation of both, the inhibition of p70(s6k), and transcription through Smad proteins is required for release of epithelial cells from TGF-beta-induced G(1) arrest. TGF-beta thereby modulates the translational and posttranscriptional control of cell cycle progression.
摘要
转化生长因子-β（TGF-β）结合后，TGF-β受体直接磷酸化并激活转录因子Smad2/3，导致G1期停滞。在此，我们提供证据表明存在第二条平行的、依赖TGF-β的细胞周期停滞途径，该途径通过抑制p70核糖体蛋白S6激酶（p70(s6k)）实现。TGF-β诱导其受体与蛋白磷酸酶2A（PP2A）-Bα结合。同时，三个PP2A亚基，即Bα、Aβ和Cα，与p70(s6k)结合，导致其去磷酸化并失活。尽管任何一条途径都足以诱导G1期停滞，但上皮细胞从TGF-β诱导的G1期停滞中释放需要同时废除这两条途径，即抑制p70(s6k)以及通过Smad蛋白进行转录。TGF-β由此调节细胞周期进程的翻译和转录后控制。
相似文献
1
TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest.转化生长因子-β通过蛋白磷酸酶2A抑制p70 S6激酶，从而诱导G(1)期阻滞。
Genes Dev. 2000 Dec 15;14(24):3093-101. doi: 10.1101/gad.854200.
2
Transforming growth factor-beta- and Activin-Smad signaling pathways are activated at distinct maturation stages of the thymopoeisis.转化生长因子-β和激活素-Smad信号通路在胸腺生成的不同成熟阶段被激活。
Int Immunol. 2003 Dec;15(12):1401-14. doi: 10.1093/intimm/dxg139.
3
Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein.蛋白磷酸酶2A与70 kDa的S6激酶相互作用，并通过抑制FKBP12-雷帕霉素相关蛋白而被激活。
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4438-42. doi: 10.1073/pnas.96.8.4438.
4
Probing the role of homomeric and heteromeric receptor interactions in TGF-beta signaling using small molecule dimerizers.利用小分子二聚体探究同聚体和异聚体受体相互作用在转化生长因子-β信号传导中的作用。
Curr Biol. 1998 Jun 18;8(13):761-70. doi: 10.1016/s0960-9822(98)70299-4.
5
Temporal activation of p70 S6 kinase and Akt1 by insulin: PI 3-kinase-dependent and -independent mechanisms.胰岛素对p70 S6激酶和Akt1的瞬时激活：PI 3激酶依赖性和非依赖性机制。
Am J Physiol. 1998 Oct;275(4):E618-25. doi: 10.1152/ajpendo.1998.275.4.E618.
6
Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors.通过两种不同的转化生长因子β I 型受体平衡内皮细胞的激活状态。
EMBO J. 2002 Apr 2;21(7):1743-53. doi: 10.1093/emboj/21.7.1743.
7
Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts.瘢痕疙瘩成纤维细胞中转化生长因子-β受体I和II的差异表达及Smad 3的激活
Plast Reconstr Surg. 2001 Aug;108(2):423-9. doi: 10.1097/00006534-200108000-00022.
8
Two highly related regulatory subunits of PP2A exert opposite effects on TGF-beta/Activin/Nodal signalling.蛋白磷酸酶2A的两个高度相关的调节亚基对转化生长因子-β/激活素/节点信号传导具有相反的作用。
Development. 2008 Sep;135(17):2927-37. doi: 10.1242/dev.020842.
9
Functional conservation of Schistosoma mansoni Smads in TGF-beta signaling.曼氏血吸虫Smads在转化生长因子-β信号传导中的功能保守性
Mol Biochem Parasitol. 2000 Nov;111(1):131-42. doi: 10.1016/s0166-6851(00)00307-8.
10
Targeting endogenous transforming growth factor beta receptor signaling in SMAD4-deficient human pancreatic carcinoma cells inhibits their invasive phenotype1.靶向SMAD4缺陷型人胰腺癌细胞中的内源性转化生长因子β受体信号传导可抑制其侵袭性表型1。
Cancer Res. 2004 Aug 1;64(15):5200-11. doi: 10.1158/0008-5472.CAN-04-0018.
引用本文的文献
1
Transforming Growth Factor-β Pathway: Biological Functions and Therapeutic Targets.转化生长因子-β信号通路：生物学功能与治疗靶点
MedComm (2020). 2025 Jun 27;6(7):e70278. doi: 10.1002/mco2.70278. eCollection 2025 Jul.
2
Macrophage Cell Cycle.巨噬细胞细胞周期。
Results Probl Cell Differ. 2024;74:119-134. doi: 10.1007/978-3-031-65944-7_4.
3
Mapping the substrate landscape of protein phosphatase 2A catalytic subunit PPP2CA.绘制蛋白磷酸酶2A催化亚基PPP2CA的底物图谱。
iScience. 2024 Feb 19;27(3):109302. doi: 10.1016/j.isci.2024.109302. eCollection 2024 Mar 15.
4
Far-Infrared Irradiation Decreases Proliferation in Basal and PDGF-Stimulated VSMCs Through AMPK-Mediated Inhibition of mTOR/p70S6K Signaling Axis.远红外辐射通过 AMPK 介导的抑制 mTOR/p70S6K 信号轴减少基础和 PDGF 刺激的 VSMCs 的增殖。
J Korean Med Sci. 2023 Oct 23;38(41):e335. doi: 10.3346/jkms.2023.38.e335.
5
The B56γ3-containing protein phosphatase 2A attenuates p70S6K-mediated negative feedback loop to enhance AKT-facilitated epithelial-mesenchymal transition in colorectal cancer.B56γ3 包含的蛋白磷酸酶 2A 减弱了 p70S6K 介导的负反馈环，从而增强了 AKT 促进的结直肠癌细胞上皮-间充质转化。
Cell Commun Signal. 2023 Jul 10;21(1):172. doi: 10.1186/s12964-023-01182-5.
6
Asymmetric Dimethylation of Ribosomal S6 Kinase 2 Regulates Its Cellular Localisation and Pro-Survival Function.核糖体 S6 激酶 2 的不对称二甲基化调节其细胞定位和促生存功能。
Int J Mol Sci. 2023 May 15;24(10):8806. doi: 10.3390/ijms24108806.
7
Embryonic organizer formation disorder leads to multiorgan dysplasia in Down syndrome.胚胎组织者形成障碍导致唐氏综合征多器官发育不良。
Cell Death Dis. 2022 Dec 19;13(12):1054. doi: 10.1038/s41419-022-05517-x.
8
Beyond controlling cell size: functional analyses of S6K in tumorigenesis.超越控制细胞大小：S6K 在肿瘤发生中的功能分析。
Cell Death Dis. 2022 Jul 25;13(7):646. doi: 10.1038/s41419-022-05081-4.
9
IGFBP-3 and TGF-β inhibit growth in epithelial cells by stimulating type V TGF-β receptor (TβR-V)-mediated tumor suppressor signaling.胰岛素样生长因子结合蛋白3（IGFBP-3）和转化生长因子-β（TGF-β）通过刺激V型转化生长因子-β受体（TβR-V）介导的肿瘤抑制信号来抑制上皮细胞生长。
FASEB Bioadv. 2021 Jun 16;3(9):709-729. doi: 10.1096/fba.2021-00016. eCollection 2021 Sep.
10
The Role of TGF- Signaling Pathways in Cancer and Its Potential as a Therapeutic Target.转化生长因子信号通路在癌症中的作用及其作为治疗靶点的潜力。
Evid Based Complement Alternat Med. 2021 Jul 22;2021:6675208. doi: 10.1155/2021/6675208. eCollection 2021.
本文引用的文献
1
Controlling TGF-beta signaling.控制转化生长因子-β信号传导。
Genes Dev. 2000 Mar 15;14(6):627-44.
2
The Smad pathway.Smad信号通路。
Cytokine Growth Factor Rev. 2000 Mar-Jun;11(1-2):5-13. doi: 10.1016/s1359-6101(99)00024-6.
3
Signaling inputs converge on nuclear effectors in TGF-beta signaling.信号输入在转化生长因子β信号通路中汇聚于核效应器。
Trends Biochem Sci. 2000 Feb;25(2):64-70. doi: 10.1016/s0968-0004(99)01519-4.
4
Regulation of protein kinase cascades by protein phosphatase 2A.蛋白磷酸酶2A对蛋白激酶级联反应的调控
Trends Biochem Sci. 1999 May;24(5):186-91. doi: 10.1016/s0968-0004(99)01375-4.
5
Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycinassociated protein.蛋白磷酸酶2A与70 kDa的S6激酶相互作用，并通过抑制FKBP12-雷帕霉素相关蛋白而被激活。
Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4438-42. doi: 10.1073/pnas.96.8.4438.
6
Targeted disruption of Smad3 reveals an essential role in transforming growth factor beta-mediated signal transduction.对Smad3进行靶向破坏揭示了其在转化生长因子β介导的信号转导中的重要作用。
Mol Cell Biol. 1999 Apr;19(4):2495-504. doi: 10.1128/MCB.19.4.2495.
7
Targeted disruption of SMAD3 results in impaired mucosal immunity and diminished T cell responsiveness to TGF-beta.SMAD3的靶向破坏导致黏膜免疫受损以及T细胞对转化生长因子-β（TGF-β）的反应性降低。
EMBO J. 1999 Mar 1;18(5):1280-91. doi: 10.1093/emboj/18.5.1280.
8
Crystal structure of the cytoplasmic domain of the type I TGF beta receptor in complex with FKBP12.I型转化生长因子β受体胞质结构域与FKBP12复合物的晶体结构
Cell. 1999 Feb 5;96(3):425-36. doi: 10.1016/s0092-8674(00)80555-3.
9
Protein phosphatase 2A: who shall regulate the regulator?蛋白磷酸酶2A：谁来调控调控因子？
Biochem Pharmacol. 1999 Feb 15;57(4):321-8. doi: 10.1016/s0006-2952(98)00245-7.
10
Role of PP2A in intracellular signal transduction pathways.蛋白磷酸酶2A在细胞内信号转导途径中的作用。
Front Biosci. 1998 Dec 15;3:D1262-73. doi: 10.2741/A361.
Zotero 插件