ATM/Chk2/p53 通路成分缺失可加速胶质瘤的发展并导致其对放疗产生抗性。
Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas.
机构信息
Department of Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
出版信息
Cancer Cell. 2010 Dec 14;18(6):619-29. doi: 10.1016/j.ccr.2010.10.034.
Abstract
Maintenance of genomic integrity is essential for adult tissue homeostasis and defects in the DNA-damage response (DDR) machinery are linked to numerous pathologies including cancer. Here, we present evidence that the DDR exerts tumor suppressor activity in gliomas. We show that genes encoding components of the DDR pathway are frequently altered in human gliomas and that loss of elements of the ATM/Chk2/p53 cascade accelerates tumor formation in a glioma mouse model. We demonstrate that Chk2 is required for glioma response to ionizing radiation in vivo and is necessary for DNA-damage checkpoints in the neuronal stem cell compartment. Finally, we observed that the DDR is constitutively activated in a subset of human GBMs, and such activation correlates with regions of hypoxia.
摘要
维持基因组完整性对于成人组织稳态至关重要，而 DNA 损伤反应 (DDR) 机制的缺陷与包括癌症在内的许多病理学有关。在这里，我们提供了证据表明 DDR 在神经胶质瘤中发挥肿瘤抑制活性。我们表明，编码 DDR 途径组成部分的基因在人类神经胶质瘤中经常发生改变，并且 ATM/Chk2/p53 级联的元件缺失会加速神经胶质瘤小鼠模型中的肿瘤形成。我们证明 Chk2 对于体内神经胶质瘤对电离辐射的反应是必需的，并且对于神经元干细胞区室中的 DNA 损伤检查点也是必需的。最后，我们观察到 DDR 在一部分人类 GBM 中持续激活，这种激活与缺氧区域相关。
相似文献
1
Loss of ATM/Chk2/p53 pathway components accelerates tumor development and contributes to radiation resistance in gliomas.
Cancer Cell. 2010 Dec 14;18(6):619-29. doi: 10.1016/j.ccr.2010.10.034.
2
ATM regulates ATR chromatin loading in response to DNA double-strand breaks.
J Exp Med. 2006 Feb 20;203(2):297-303. doi: 10.1084/jem.20051923. Epub 2006 Feb 6.
3
Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner.
Mol Cell Biol. 2002 Sep;22(18):6521-32. doi: 10.1128/MCB.22.18.6521-6532.2002.
4
The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer.
Adv Cancer Res. 2010;108:73-112. doi: 10.1016/B978-0-12-380888-2.00003-0.
5
Role of ATM and the damage response mediator proteins 53BP1 and MDC1 in the maintenance of G(2)/M checkpoint arrest.
Mol Cell Biol. 2010 Jul;30(13):3371-83. doi: 10.1128/MCB.01644-09. Epub 2010 Apr 26.
6
The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis.
Nature. 2001 Apr 12;410(6830):842-7. doi: 10.1038/35071124.
7
Ataxia telangiectasia-mutated protein can regulate p53 and neuronal death independent of Chk2 in response to DNA damage.
J Biol Chem. 2003 Sep 26;278(39):37782-9. doi: 10.1074/jbc.M304049200. Epub 2003 Jul 11.
8
An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells.
Cell Host Microbe. 2010 Dec 16;8(6):510-22. doi: 10.1016/j.chom.2010.11.004.
9
Osteoblasts survive the arsenic trioxide treatment by activation of ATM-mediated pathway.
Biochem Pharmacol. 2013 Apr 1;85(7):1018-26. doi: 10.1016/j.bcp.2013.01.008. Epub 2013 Jan 18.
10
ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency.
EMBO J. 2006 May 17;25(10):2167-77. doi: 10.1038/sj.emboj.7601115. Epub 2006 May 4.
引用本文的文献
1
Comprehensive analysis of regulated cell death pathways: intrinsic disorder, protein-protein interactions, and cross-pathway communication.
Apoptosis. 2025 Aug 19. doi: 10.1007/s10495-025-02161-6.
2
ATM is associated with the prognosis of colorectal cancer: a systematic review.
Front Oncol. 2025 Mar 12;15:1470939. doi: 10.3389/fonc.2025.1470939. eCollection 2025.
3
Glioblastoma multiforme: insights into pathogenesis, key signaling pathways, and therapeutic strategies.
Mol Cancer. 2025 Feb 26;24(1):58. doi: 10.1186/s12943-025-02267-0.
4
REV7: a small but mighty regulator of genome maintenance and cancer development.
Front Oncol. 2025 Jan 7;14:1516165. doi: 10.3389/fonc.2024.1516165. eCollection 2024.
5
ATRX loss inhibits DDR to strengthen radio-sensitization in p53-deficent HCT116 cells.
Sci Rep. 2025 Jan 4;15(1):793. doi: 10.1038/s41598-024-85085-6.
6
Genomic predictors of radiation response: recent progress towards personalized radiotherapy for brain metastases.
Cell Death Discov. 2024 Dec 18;10(1):501. doi: 10.1038/s41420-024-02270-2.
7
Regulation of p53 by the mitotic surveillance/stopwatch pathway: implications in neurodevelopment and cancer.
Front Cell Dev Biol. 2024 Sep 27;12:1451274. doi: 10.3389/fcell.2024.1451274. eCollection 2024.
8
Pre-Clinical Models for CAR T-Cell Therapy for Glioma.
Cells. 2024 Sep 4;13(17):1480. doi: 10.3390/cells13171480.
9
Chromosomal instability: a key driver in glioma pathogenesis and progression.
Eur J Med Res. 2024 Sep 4;29(1):451. doi: 10.1186/s40001-024-02043-8.
10
Glioblastoma modeling with 3D organoids: progress and challenges.
Oxf Open Neurosci. 2023 Jul 6;2:kvad008. doi: 10.1093/oons/kvad008. eCollection 2023.
本文引用的文献
1
Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas.
Oncogene. 2010 Sep 9;29(36):5095-102. doi: 10.1038/onc.2010.249. Epub 2010 Jun 28.
2
Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells.
Cell Stem Cell. 2010 Feb 5;6(2):141-52. doi: 10.1016/j.stem.2010.01.001.
3
Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.
Cancer Cell. 2010 Jan 19;17(1):98-110. doi: 10.1016/j.ccr.2009.12.020.
4
Chk2 down-regulation by promoter hypermethylation in human bulk gliomas.
Life Sci. 2010 Jan 30;86(5-6):185-91. doi: 10.1016/j.lfs.2009.11.023. Epub 2009 Dec 5.
5
Glioblastoma subclasses can be defined by activity among signal transduction pathways and associated genomic alterations.
PLoS One. 2009 Nov 13;4(11):e7752. doi: 10.1371/journal.pone.0007752.
6
The DNA-damage response in human biology and disease.
Nature. 2009 Oct 22;461(7267):1071-8. doi: 10.1038/nature08467.
7
Taking the time to make important decisions: the checkpoint effector kinases Chk1 and Chk2 and the DNA damage response.
DNA Repair (Amst). 2009 Sep 2;8(9):1047-54. doi: 10.1016/j.dnarep.2009.04.012. Epub 2009 May 26.
8
PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells.
Cell Stem Cell. 2009 Mar 6;4(3):226-35. doi: 10.1016/j.stem.2009.01.007.
9
Genetically engineered mouse models of brain cancer and the promise of preclinical testing.
Brain Pathol. 2009 Jan;19(1):132-43. doi: 10.1111/j.1750-3639.2008.00234.x.
10
ATM activation and signaling under hypoxic conditions.
Mol Cell Biol. 2009 Jan;29(2):526-37. doi: 10.1128/MCB.01301-08. Epub 2008 Nov 3.
Zotero 插件