CSN6 drives carcinogenesis by positively regulating Myc stability

被引：71

作者：

Chen, Jian ^{[1
]}

Shin, Ji-Hyun ^{[1
]}

Zhao, Ruiying ^{[1
]}

Liem Phan ^{[1
]}

Wang, Hua ^{[2
]}

Xue, Yuwen ^{[1
]}

Post, Sean M. ^{[3
]}

Choi, Hyun Ho ^{[1
]}

Chen, Jiun-Sheng ^{[1
]}

Wang, Edward ^{[1
]}

Zhou, Zhongguo ^{[1
]}

Tseng, Chieh ^{[1
]}

Gully, Christopher ^{[1
]}

Velazquez-Torres, Guermarie ^{[1
]}

Fuentes-Mattei, Enrique ^{[1
]}

Yeung, Giselle ^{[1
]}

Qiao, Yi ^{[1
]}

Chou, Ping-Chieh ^{[1
]}

Su, Chun-Hui ^{[1
]}

Hsieh, Yun-Chih ^{[1
]}

Hsu, Shih-Lan ^{[4
]}

Ohshiro, Kazufumi ^{[1
]}

Shaikenov, Tattym ^{[1
]}

Wang, Huamin ^{[5
]}

Yeung, Sai-Ching Jim ^{[6
,7
]}

Lee, Mong-Hong ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept GI Med Oncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA

[4] Taichung Vet Gen Hosp, Dept Educ & Res, Taichung 40705, Taiwan

[5] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[6] Univ Texas MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA

[7] Univ Texas MD Anderson Canc Ctr, Dept Emergency Med, Houston, TX 77030 USA

来源：

NATURE COMMUNICATIONS | 2014年 / 5卷

基金：

美国国家卫生研究院;

关键词：

COP9 SIGNALOSOME SUBUNIT-6; FBW7 UBIQUITIN LIGASE; C-MYC; GENE-EXPRESSION; LIGHT CONTROL; DEGRADATION; ARABIDOPSIS; COMPLEX; CANCER; NEDD8;

D O I：

10.1038/ncomms6384

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Cullin-RING ubiquitin ligases (CRLs) are critical in ubiquitinating Myc, while COP9 signalosome (CSN) controls neddylation of Cullin in CRL. The mechanistic link between Cullin neddylation and Myc ubiquitination/degradation is unclear. Here we show that Myc is a target of the CSN subunit 6 (CSN6)-Cullin signalling axis and that CSN6 is a positive regulator of Myc. CSN6 enhanced neddylation of Cullin-1 and facilitated autoubiquitination/degradation of Fbxw7, a component of CRL involved in Myc ubiquitination, thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation but increased Fbxw7 stability to compromise Myc stability and activity in an E mu-Myc mouse model, resulting in decelerated lymphomagenesis. We found that CSN6 overexpression, which leads to aberrant expression of Myc target genes, is frequent in human cancers. Together, these results define a mechanism for the regulation of Myc stability through the CSN-Cullin-Fbxw7 axis and provide insights into the correlation of CSN6 overexpression with Myc stabilization/activation during tumorigenesis.

引用

页数：15

共 60 条

[1]

THE C-MYC ONCOGENE DRIVEN BY IMMUNOGLOBULIN ENHANCERS INDUCES LYMPHOID MALIGNANCY IN TRANSGENIC MICE [J].

ADAMS, JM ;

HARRIS, AW ;

PINKERT, CA ;

CORCORAN, LM ;

ALEXANDER, WS ;

CORY, S ;

PALMITER, RD ;

BRINSTER, RL .

NATURE, 1985, 318 (6046) :533-538

[2]

Transcriptional regulation and transformation by MYC proteins [J].

Adhikary, S ;

Eilers, M .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2005, 6 (08) :635-645

[3]

Genetic regulators of large-scale transcriptional signatures in cancer [J].

Adler, AS ;

Lin, MH ;

Horlings, H ;

Nuyten, DSA ;

van de Vijver, MJ ;

Chang, HY .

NATURE GENETICS, 2006, 38 (04) :421-430

[4]

c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression [J].

Baudino, TA ;

McKay, C ;

Pendeville-Samain, H ;

Nilsson, JA ;

Maclean, KH ;

White, EL ;

Davis, AC ;

Ihle, JN ;

Cleveland, JL .

GENES & DEVELOPMENT, 2002, 16 (19) :2530-2543

[5]

Dynamics of Cullin-RING Ubiquitin Ligase Network Revealed by Systematic Quantitative Proteomics [J].

Bennett, Eric J. ;

Rush, John ;

Gygi, Steven P. ;

Harper, J. Wade .

CELL, 2010, 143 (06) :951-965

[6]

Nucleophosmin and its AML-associated mutant regulate c-Myc turnover through Fbw7γ [J].

Bonetti, Paola ;

Davoli, Teresa ;

Sironi, Cristina ;

Amati, Bruno ;

Pelicci, Pier Giuseppe ;

Colombo, Emanuela .

JOURNAL OF CELL BIOLOGY, 2008, 182 (01) :19-26

[7]

The SCF ubiquitin ligase: Insights into a molecular machine [J].

Cardozo, T ;

Pagano, M .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2004, 5 (09) :739-751

[8]

The COP9 complex, a novel multisubunit nuclear regulator involved in light control of a plant developmental switch [J].

Chamovitz, DA ;

Wei, N ;

Osterlund, MT ;

vonArnim, AG ;

Staub, JM ;

Matsui, M ;

Deng, XW .

CELL, 1996, 86 (01) :115-121

[9]

CDK inhibitor p57Kip2 is negatively regulated by COP9 signalosome subunit 6 [J].

Chen, Bo ;

Zhao, Ruiying ;

Su, Chun-Hui ;

Linan, Monica ;

Tseng, Chieh ;

Phan, Liem ;

Fang, Lekuan ;

Yang, Heng-Yin ;

Yang, Huiling ;

Wang, Wenqian ;

Xu, Xiaoyin ;

Jiang, Nan ;

Cai, Shouliang ;

Jin, Feng ;

Yeung, Sai-Ching J. ;

Lee, Mong-Hong .

CELL CYCLE, 2012, 11 (24) :4633-4641

[10]

COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ [J].

Choi, H. H. ;

Gully, C. ;

Su, C-H ;

Velazquez-Torres, G. ;

Chou, P-C ;

Tseng, C. ;

Zhao, R. ;

Phan, L. ;

Shaiken, T. ;

Chen, J. ;

Yeung, S. C. ;

Lee, M-H .

ONCOGENE, 2011, 30 (48) :4791-4801

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