Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins

被引：145

作者：

Gong, Yongxing ^{[1
]}

Zack, Travis Ian ^{[2
,3
,4
,5
,6
]}

Morris, Luc G. T. ^{[7
]}

Lin, Kan ^{[8
]}

Hukkelhoven, Ellen ^{[9
]}

Raheja, Radhika ^{[9
]}

Tan, I-Li ^{[8
]}

Turcan, Sevin ^{[1
]}

Veeriah, Selvaraju ^{[1
]}

Meng, Shasha ^{[1
]}

Viale, Agnes ^{[10
]}

Schumacher, Steven E. ^{[2
]}

Palmedo, Perry ^{[2
,11
]}

Beroukhim, Rameen ^{[2
,3
,4
,5
]}

Chan, Timothy A. ^{[1
,12
,13
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[2] Broad Inst, Cambridge, MA USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[5] Dana Farber Canc Inst, Ctr Canc Genome Characterizat, Boston, MA 02115 USA

[6] Harvard Univ, Biophys Program, Boston, MA 02115 USA

[7] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA

[8] Weill Cornell Coll Med, New York, NY USA

[9] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA

[10] Mem Sloan Kettering Canc Ctr, Genom Core, New York, NY 10021 USA

[11] Harvard Univ, Ctr Biomed Informat, Boston, MA 02115 USA

[12] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA

[13] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10021 USA

来源：

NATURE GENETICS | 2014年 / 46卷 / 06期

基金：

美国国家卫生研究院;

关键词：

COPY-NUMBER ALTERATION; F-BOX PROTEINS; CELL-CYCLE; UBIQUITIN LIGASES; MITOCHONDRIAL DEPOLARIZATION; COLORECTAL-CANCER; TUMOR-SUPPRESSOR; BREAST-CANCER; DEGRADATION; D1;

D O I：

10.1038/ng.2981

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Coordinate control of different classes of cyclins is fundamentally important for cell cycle regulation and tumor suppression, yet the underlying mechanisms are incompletely understood. Here we show that the PARK2 tumor suppressor mediates this coordination. The PARK2 E3 ubiquitin ligase coordinately controls the stability of both cyclin D and cyclin E. Analysis of approximately 5,000 tumor genomes shows that PARK2 is a very frequently deleted gene in human cancer and uncovers a striking pattern of mutual exclusivity between PARK2 deletion and amplification of CCND1, CCNE1 or CDK4-implicating these genes in a common pathway. Inactivation of PARK2 results in the accumulation of cyclin D and acceleration of cell cycle progression. Furthermore, PARK2 is a component of a new class of cullin-RING-containing ubiquitin ligases targeting both cyclin D and cyclin E for degradation. Thus, PARK2 regulates cyclin-CDK complexes, as does the CDK inhibitor p16, but acts as a master regulator of the stability of G1/S cyclins.

引用

页码：588 / 594

页数：7

共 53 条

[1] Citron kinase is required for postnatal neurogenesis in the hippocampus [J].

Ackman, James B. ;

Ramos, Raddy L. ;

Sarkisian, Matthew R. ;

LoTurco, Joseph J. .

DEVELOPMENTAL NEUROSCIENCE, 2007, 29 (1-2) :113-123

[2] Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation [J].

Alt, JR ;

Cleveland, JL ;

Hannink, M ;

Diehl, JA .

GENES & DEVELOPMENT, 2000, 14 (24) :3102-3114

[3] Gene amplification and overexpression of CDK4 in sporadic breast carcinomas is associated with high tumor cell proliferation [J].

An, HX ;

Beckmann, MW ;

Reifenberger, G ;

Bender, HG ;

Niederacher, D .

AMERICAN JOURNAL OF PATHOLOGY, 1999, 154 (01) :113-118

[4] SCF-mediated protein degradation and cell cycle control [J].

Ang, XLL ;

Harper, JW .

ONCOGENE, 2005, 24 (17) :2860-2870

[5] Mutations in Fbx4 inhibit dimerization of the SCFFbx4 ligase and contribute to cyclin D1 overexpression in human cancer [J].

Barbash, Olena ;

Zamfirova, Petia ;

Lin, Douglas I. ;

Chen, Xiangmei ;

Yang, Ke ;

Nakagawa, Hiroshi ;

Lu, Fengmin ;

Rustgi, Anil K. ;

Diehl, J. Alan .

CANCER CELL, 2008, 14 (01) :68-78

[6] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[7] Signatures of mutation and selection in the cancer genome [J].

Bignell, Graham R. ;

Greenman, Chris D. ;

Davies, Helen ;

Butler, Adam P. ;

Edkins, Sarah ;

Andrews, Jenny M. ;

Buck, Gemma ;

Chen, Lina ;

Beare, David ;

Latimer, Calli ;

Widaa, Sara ;

Hinton, Jonathon ;

Fahey, Ciara ;

Fu, Beiyuan ;

Swamy, Sajani ;

Dalgliesh, Gillian L. ;

Teh, Bin T. ;

Deloukas, Panos ;

Yang, Fengtang ;

Campbell, Peter J. ;

Futreal, P. Andrew ;

Stratton, Michael R. .

NATURE, 2010, 463 (7283) :893-U61

[8] Mutual exclusivity analysis identifies oncogenic network modules [J].

Ciriello, Giovanni ;

Cerami, Ethan ;

Sander, Chris ;

Schultz, Nikolaus .

GENOME RESEARCH, 2012, 22 (02) :398-406

[9] SCF and cullin/RING H2-based ubiquitin ligases [J].

Deshaies, RJ .

ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, 1999, 15 :435-467

[10] Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquintin-proteasome pathway [J].

Diehl, JA ;

Zindy, F ;

Sherr, CJ .

GENES & DEVELOPMENT, 1997, 11 (08) :957-972

← 1 2 3 4 5 6 →