同期2篇Nature谱写癌基因RAS新靶位

【字体: 时间:2009年11月11日 来源:生物通

编辑推荐:

  生物通报道,最新一期的Nature发布了两篇关于RAS癌基因的下游靶位文章,一篇是麻省理工大学发表的Requirement for NF-B signalling in a mouse model of lung adenocarcinoma,一篇是哈佛医学院发表的Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1。

  

生物通报道,最新一期的Nature发布了两篇关于RAS癌基因的下游靶位文章,一篇是麻省理工大学发表的Requirement for NF-B signalling in a mouse model of lung adenocarcinoma,一篇是哈佛医学院发表的Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1

 

Ras癌基因参与人类肿瘤的发生发展,它最初是在急性转化性逆转录病毒实验中,从HarveyKirsten两株大鼠肉瘤病毒中克隆出的转化基因,自82Weinberg等人发现人膀胱癌细胞系中有活化的H-ras基因后,引起了人们对ras癌基因在人类肿瘤发生、发展中所起作用的极大关注.经十余年研究认为,ras癌基因参予细胞生长和分化的调控,参与多种肿瘤的形成与发展.

 

RAS基因的突变率为20%,这使得ras成为癌症治疗的首选潜在靶位。遗憾的是,多年过去了,以ras蛋白为癌症治疗靶位的研究一直没有进展,抑癌效果一直不佳。

 

而最新一期的Nature上发表的两篇文章,让我们看到了新的希望,位于Ras下游的其他转导信号通路成为具有潜力的新癌症靶位。

 

哈佛医学院Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1文章,揭示了KRAS驱动的癌症机制中一种起关键作用的激酶TBK1.

 

TBK1NF-κB信号通道中的一种激酶,哈佛医学院的科学家用RNAi筛选发现,在KRAS突变驱动的癌变过程中,TBK1发挥了不可或缺的作用,它是被KRAS-改变的细胞存活所必不可少的。TBK1NF-κB共同作用于KRAS介导的癌变过程中。TBK1诱导反凋亡信号,可能是一个癌症治疗目标。

 

麻省理工Requirement for NF-B signalling in a mouse model of lung adenocarcinoma文章,揭示了KRAS突变和p53缺失是导致小鼠肺部癌变的内部机制。

 

麻省理工的科学家以小鼠为模型,研究发现由Kras突变和p53丧失造成小鼠肺部癌变。Krasp53同时缺陷激发NF-κB信号作用是发生改变,这种改变是激发肿瘤发生和维持癌症进程所必须的信号。

 

关于Ras基因与癌症

82年以来,已经在膀胱癌、乳腺症、结肠癌、肾癌、肝癌、肺癌、胰腺癌、胃 癌、及造血系肿统瘤中,均检测出了ras癌基因的异常.Pulciani等的研究结果表明, 被检肿瘤DNA中所含活化ras基因仅占1020%,似乎ras癌基因在人类肿瘤发生发展中 并非起主要作用.事实上,ras癌基因参予多种肿瘤的发生发展,只不过突变率相差很 .(1)不同肿瘤类型,ras癌基因的突变率相差明显,如最高可达90%(胰腺癌),其次 是甲状腺癌(53%)和结肠癌(47%).(2)突变ras癌基因的种类与某些肿病类型密切相 关,即有优势激活现象.如胰腺癌、结肠癌、肺癌等以K-ras突变为主,造血系统肿瘤 多发现N-ras的突变,泌尿系肿瘤则以H-ras突变为主,目前的资料表明,rasHrasK 的表达不仅与膀胱癌、肾盂癌、肺癌、结肠癌、有密切的关系,而且也与胆囊癌、胰 腺癌、肾母细胞癌、慢性淋巴细胞白血病,黑色素瘤形成密切相关,N-ras表达水平 上升虽然主要发生在造血系统的恶性肿瘤中,如APLAMLBL,但在神经母细胞瘤、 纤维肉瘤,横纹肌肉瘤中的表达也有一定的上升,并认为是这些肿瘤形成的主要原 因。因此,检测ras突变对了解肿瘤的发生发展,以及监测恶性肿瘤的治疗效果具有 重大意义,对临床工作具有重要指导意义.

(生物通 小茜)

生物通推荐原文检索

Requirement for NF-B signalling in a mouse model of lung adenocarcinoma

Etienne Meylan1, Alison L. Dooley1, David M. Feldser1, Lynn Shen1, Erin Turk1, Chensi Ouyang1 & Tyler Jacks1

 

Koch Institute for Integrative Cancer Research, and Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

Correspondence to: Tyler Jacks1 Correspondence and requests for materials should be addressed to T.J. (Email: tjacks@mit.edu).

 

Abstract

NF-B transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival1. They have also been implicated in cellular transformation and tumorigenesis2, 3, 4, 5, 6. However, despite extensive biochemical characterization of NF-B signalling during the past twenty years, the requirement for NF-B in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-B pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-B activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-B inhibition. Furthermore, the inhibition of NF-B signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-B signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-B inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.

 

Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1

David A. Barbie1,3,4, Pablo Tamayo3, Jesse S. Boehm3, So Young Kim1,2, Susan E. Moody1,3, Ian F. Dunn1,3,5, Anna C. Schinzel1,3, Peter Sandy7,8, Etienne Meylan7,8, Claudia Scholl6, Stefan Fröhling6, Edmond M. Chan3, Martin L. Sos9, Kathrin Michel9, Craig Mermel1,3, Serena J. Silver3, Barbara A. Weir3, Jan H. Reiling7,10, Qing Sheng1, Piyush B. Gupta3, Raymond C. Wadlow3,4, Hanh Le3, Sebastian Hoersch8, Ben S. Wittner3,4, Sridhar Ramaswamy3,4, David M. Livingston1, David M. Sabatini3,7,10,11, Matthew Meyerson1,2,3, Roman K. Thomas9,12,13, Eric S. Lander3,7, Jill P. Mesirov3, David E. Root3, D. Gary Gilliland1,3,6,11, Tyler Jacks3,7,8,11 & William C. Hahn1,2,3,6

 

Department of Medical Oncology,

Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115 USA

Broad Institute of Harvard and M.I.T., 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA

Department of Neurosurgery,

Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

Department of Biology, M.I.T., 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA

Koch Institute for Integrative Cancer Research, 40 Ames Street, Cambridge, Massachusetts 02142, USA

Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Köln, Gleueler Str. 50, 50931 Köln, Germany

Whitehead Institute of Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA

Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA

Department I of Internal Medicine and Center of Integrated Oncology, University of Köln, Gleueler Str. 50, 50931 Köln, Germany

Chemical Genomics Center of the Max-Planck-Society, Otto-Hahn-Str. 15, 44227 Dortmund, Germany

Correspondence to: William C. Hahn1,2,3,6 Correspondence and requests for materials should be addressed to W.C.H. (Email: william_hahn@dfci.harvard.edu).

 

Abstract

The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele1, 2. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-B anti-apoptotic

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