• 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

p16Ink4a的实时体内成像揭示了与p53的相互作用。

Real-time in vivo imaging of p16Ink4a reveals cross talk with p53.

作者信息

Yamakoshi Kimi, Takahashi Akiko, Hirota Fumiko, Nakayama Rika, Ishimaru Naozumi, Kubo Yoshiaki, Mann David J, Ohmura Masako, Hirao Atsushi, Saya Hideyuki, Arase Seiji, Hayashi Yoshio, Nakao Kazuki, Matsumoto Mitsuru, Ohtani Naoko, Hara Eiji

机构信息

The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.

出版信息

J Cell Biol. 2009 Aug 10;186(3):393-407. doi: 10.1083/jcb.200904105.

DOI:10.1083/jcb.200904105
PMID:19667129
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2728398/
Abstract

Expression of the p16(Ink4a) tumor suppressor gene, a sensor of oncogenic stress, is up-regulated by a variety of potentially oncogenic stimuli in cultured primary cells. However, because p16(Ink4a) expression is also induced by tissue culture stress, physiological mechanisms regulating p16(Ink4a) expression remain unclear. To eliminate any potential problems arising from tissue culture-imposed stress, we used bioluminescence imaging for noninvasive and real-time analysis of p16(Ink4a) expression under various physiological conditions in living mice. In this study, we show that oncogenic insults such as ras activation provoke epigenetic derepression of p16(Ink4a) expression through reduction of DNMT1 (DNA methyl transferase 1) levels as a DNA damage response in vivo. This pathway is accelerated in the absence of p53, indicating that p53 normally holds the p16(Ink4a) response in check. These results unveil a backup tumor suppressor role for p16(Ink4a) in the event of p53 inactivation, expanding our understanding of how p16(Ink4a) expression is regulated in vivo.

摘要

p16(Ink4a)肿瘤抑制基因作为致癌应激的一种感受器，其表达在培养的原代细胞中会被多种潜在致癌刺激上调。然而，由于p16(Ink4a)的表达也会被组织培养应激所诱导，因此调节p16(Ink4a)表达的生理机制仍不清楚。为了消除组织培养应激带来的任何潜在问题，我们利用生物发光成像技术对活体小鼠在各种生理条件下p16(Ink4a)的表达进行非侵入性实时分析。在本研究中，我们发现致癌性损伤（如ras激活）会通过降低DNMT1（DNA甲基转移酶1）水平，作为体内DNA损伤反应，引发p16(Ink4a)表达的表观遗传去抑制。在缺乏p53的情况下，这一途径会加速，表明p53通常会抑制p16(Ink4a)反应。这些结果揭示了在p53失活情况下p16(Ink4a)的备用肿瘤抑制作用，扩展了我们对p16(Ink4a)在体内表达调控方式的理解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/f7ce8b413630/JCB_200904105_LW_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/00d4376fb6b7/JCB_200904105_RGB_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/df4ca48cff75/JCB_200904105_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/ad691442bc47/JCB_200904105_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/2d17cf34af65/JCB_200904105_RGB_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/7de142f6c7e7/JCB_200904105_LW_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/e8c4caacf8f0/JCB_200904105_GS_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/7e10c3cef96b/JCB_200904105_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/9c2bb6707831/JCB_200904105_RGB_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/f7ce8b413630/JCB_200904105_LW_Fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/00d4376fb6b7/JCB_200904105_RGB_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/df4ca48cff75/JCB_200904105_RGB_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/ad691442bc47/JCB_200904105_RGB_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/2d17cf34af65/JCB_200904105_RGB_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/7de142f6c7e7/JCB_200904105_LW_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/e8c4caacf8f0/JCB_200904105_GS_Fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/7e10c3cef96b/JCB_200904105_RGB_Fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/9c2bb6707831/JCB_200904105_RGB_Fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7b9b/2728398/f7ce8b413630/JCB_200904105_LW_Fig9.jpg

相似文献

1
Real-time in vivo imaging of p16Ink4a reveals cross talk with p53.p16Ink4a的实时体内成像揭示了与p53的相互作用。
J Cell Biol. 2009 Aug 10;186(3):393-407. doi: 10.1083/jcb.200904105.
2
p16 enhances the transcriptional and the apoptotic functions of p53 through DNA-dependent interaction.p16通过依赖DNA的相互作用增强p53的转录和凋亡功能。
Mol Carcinog. 2017 Jul;56(7):1687-1702. doi: 10.1002/mc.22627. Epub 2017 Mar 6.
3
Resistance of primary cultured mouse hepatic tumor cells to cellular senescence despite expression of p16(Ink4a), p19(Arf), p53, and p21(Waf1/Cip1).原代培养的小鼠肝癌细胞尽管表达了p16(Ink4a)、p19(Arf)、p53和p21(Waf1/Cip1)，但对细胞衰老具有抗性。
Mol Carcinog. 2001 Sep;32(1):9-18. doi: 10.1002/mc.1059.
4
P16(INK4A) is implicated in both the immediate and adaptative response of human keratinocytes to UVB irradiation.P16（INK4A）在人类角质形成细胞对紫外线B照射的即时反应和适应性反应中均有涉及。
Oncogene. 2002 Apr 18;21(17):2652-61. doi: 10.1038/sj.onc.1205349.
5
p16(Ink4a) and senescence-associated β-galactosidase can be induced in macrophages as part of a reversible response to physiological stimuli.p16（Ink4a）和衰老相关β半乳糖苷酶可在巨噬细胞中被诱导产生，作为对生理刺激的可逆反应的一部分。
Aging (Albany NY). 2017 Aug 2;9(8):1867-1884. doi: 10.18632/aging.101268.
6
Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific siRNA in vitro.体外p16INK4a特异性小干扰RNA诱导骨关节炎软骨细胞功能恢复
Rheumatology (Oxford). 2004 May;43(5):555-68. doi: 10.1093/rheumatology/keh127. Epub 2004 Mar 16.
7
p53 Deficiency leads to compensatory up-regulation of p16INK4a.p53基因缺失导致p16INK4a的代偿性上调。
Mol Cancer Res. 2009 Mar;7(3):354-60. doi: 10.1158/1541-7786.MCR-08-0373. Epub 2009 Feb 24.
8
DNA (cytosine-5)-methyltransferase 1 as a mediator of mutant p53-determined p16(ink4A) down-regulation.DNA（胞嘧啶-5）-甲基转移酶1作为突变型p53所致p16（ink4A）下调的介质。
J Biomed Sci. 2008 Mar;15(2):163-8. doi: 10.1007/s11373-007-9222-y. Epub 2007 Nov 24.
9
Dual inactivation of RB and p53 pathways in RAS-induced melanomas.RAS诱导的黑色素瘤中RB和p53通路的双重失活。
Mol Cell Biol. 2001 Mar;21(6):2144-53. doi: 10.1128/MCB.21.6.2144-2153.2001.
10
The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence.p53和pRb信号通路在癌基因诱导的黑素细胞衰老中的相对作用。
Aging (Albany NY). 2009 May 16;1(6):542-56. doi: 10.18632/aging.100051.

引用本文的文献

1
Hydrogen Peroxide-Releasing Hydrogel-Mediated Cellular Senescence Model for Aging Research.用于衰老研究的过氧化氢释放水凝胶介导的细胞衰老模型
Biomater Res. 2025 Mar 14;29:0161. doi: 10.34133/bmr.0161. eCollection 2025.
2
Senolytic treatment for low back pain.用于治疗腰痛的衰老细胞溶解疗法。
Sci Adv. 2025 Mar 14;11(11):eadr1719. doi: 10.1126/sciadv.adr1719.
3
Cellular senescence: mechanisms and relevance to cancer and aging.细胞衰老：机制及其与癌症和衰老的关联

本文引用的文献

1
Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS.组蛋白去甲基化酶JMJD3通过致癌性RAS参与INK4a/ARF的表观遗传调控。
Genes Dev. 2009 May 15;23(10):1177-82. doi: 10.1101/gad.511109.
2
The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence.H3K27me3去甲基化酶JMJD3有助于INK4A-ARF基因座在致癌基因和应激诱导的衰老反应中被激活。
Genes Dev. 2009 May 15;23(10):1171-6. doi: 10.1101/gad.510809.
3
Epigenetic silencing of the p16(INK4a) tumor suppressor is associated with loss of CTCF binding and a chromatin boundary.
J Biochem. 2025 Mar 4;177(3):163-169. doi: 10.1093/jb/mvae079.
4
p16-induced senescence in cultured mast cells as a model for ageing reveals significant morphological and functional changes.以培养的肥大细胞中p16诱导的衰老作为衰老模型，揭示了显著的形态和功能变化。
Immun Ageing. 2024 Nov 11;21(1):77. doi: 10.1186/s12979-024-00478-5.
5
Mitochondrial fatty acid oxidation drives senescence.线粒体脂肪酸氧化驱动衰老。
Sci Adv. 2024 Oct 25;10(43):eado5887. doi: 10.1126/sciadv.ado5887.
6
B cell senescence promotes age-related changes in oral microbiota.B细胞衰老促进口腔微生物群与年龄相关的变化。
Aging Cell. 2024 Dec;23(12):e14304. doi: 10.1111/acel.14304. Epub 2024 Aug 9.
7
Guidelines for minimal information on cellular senescence experimentation in vivo.体内细胞衰老实验的最低信息指南。
Cell. 2024 Aug 8;187(16):4150-4175. doi: 10.1016/j.cell.2024.05.059.
8
Revolutionizing Senescence Detection: Advancements from Traditional Methods to Cutting-Edge Techniques.衰老检测的变革：从传统方法到前沿技术的进步。
Aging Dis. 2024 Jul 1;16(3):1285-1301. doi: 10.14336/AD.202.0565.
9
Podoplanin depletion in tonsil-derived mesenchymal stem cells induces cellular senescence via regulation of the p16/Rb pathway.扁桃体来源的间充质干细胞中血小板源性生长因子受体β的缺失通过p16/Rb通路的调节诱导细胞衰老。
Cell Commun Signal. 2024 Jun 12;22(1):323. doi: 10.1186/s12964-024-01705-8.
10
Dipeptidylpeptidase-4-targeted activatable fluorescent probes visualize senescent cells.二肽基肽酶-4 靶向激活型荧光探针可可视化衰老细胞。
Cancer Sci. 2024 Aug;115(8):2762-2773. doi: 10.1111/cas.16229. Epub 2024 May 27.
p16(INK4a)肿瘤抑制因子的表观遗传沉默与CTCF结合丧失及染色质边界有关。
Mol Cell. 2009 May 15;34(3):271-84. doi: 10.1016/j.molcel.2009.04.001.
4
Anti-aging activity of the Ink4/Arf locus.Ink4/Arf基因座的抗衰老活性。
Aging Cell. 2009 Apr;8(2):152-61. doi: 10.1111/j.1474-9726.2009.00458.x.
5
Ndy1/KDM2B immortalizes mouse embryonic fibroblasts by repressing the Ink4a/Arf locus.Ndy1/KDM2B 通过抑制Ink4a/Arf基因座使小鼠胚胎成纤维细胞永生化。
Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2641-6. doi: 10.1073/pnas.0813139106. Epub 2009 Feb 6.
6
The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system.RB肿瘤抑制通路在造血系统氧化应激反应中的作用。
Nat Rev Cancer. 2008 Oct;8(10):769-81. doi: 10.1038/nrc2504. Epub 2008 Sep 18.
7
Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency.p16Ink4a和p19Arf在BubR1功能不足引起的衰老和老化过程中的相反作用。
Nat Cell Biol. 2008 Jul;10(7):825-36. doi: 10.1038/ncb1744. Epub 2008 May 30.
8
The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss.Mdm2缺失或p16INK4a缺失可缓解突变型p53的固有不稳定性。
Genes Dev. 2008 May 15;22(10):1337-44. doi: 10.1101/gad.1662908.
9
Transcriptional control of human p53-regulated genes.人类p53调控基因的转录控制
Nat Rev Mol Cell Biol. 2008 May;9(5):402-12. doi: 10.1038/nrm2395.
10
Feedback circuit among INK4 tumor suppressors constrains human glioblastoma development.INK4肿瘤抑制因子之间的反馈回路限制了人类胶质母细胞瘤的发展。
Cancer Cell. 2008 Apr;13(4):355-64. doi: 10.1016/j.ccr.2008.02.010.