A Systematic Screen for CDK4/6 Substrates Links FOXM1 Phosphorylation to Senescence Suppression in Cancer Cells

被引：453

作者：

Anders, Lars ^{[1
,3
]}

Ke, Nan ^{[1
,3
]}

Hydbring, Per ^{[1
,3
]}

Choi, Yoon J. ^{[1
,3
]}

Widlund, Hans R. ^{[5
]}

Chick, Joel M. ^{[4
]}

Zhai, Huili ^{[6
]}

Vidal, Marc ^{[1
,2
,3
]}

Gygi, Stephen P. ^{[4
]}

Braun, Pascal ^{[1
,2
,3
]}

Sicinski, Piotr ^{[1
,3
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[2] Dana Farber Canc Inst, CCSB, Boston, MA 02215 USA

[3] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA

[6] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

来源：

CANCER CELL | 2011年 / 20卷 / 05期

关键词：

TRANSCRIPTION FACTOR FOXM1C; CELLULAR SENESCENCE; BREAST-CANCER; TUMOR-SUPPRESSOR; CYCLIN; PROGRESSION; INHIBITION; TRANSITION; MECHANISMS; MELANOMA;

D O I：

10.1016/j.ccr.2011.10.001

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Cyclin D-dependent kinases (CDK4 and CDK6) are positive regulators of cell cycle entry and they are over-active in the majority of human cancers. However, it is currently not completely understood by which cellular mechanisms CDK4/6 promote tumorigenesis, largely due to the limited number of identified substrates. Here we performed a systematic screen for substrates of cyclin D1-CDK4 and cyclin D3-CDK6. We identified the Forkhead Box M1 (FOXM1) transcription factor as a common critical phosphorylation target. CDK4/6 stabilize and activate FOXM1, thereby maintain expression of G1/S phase genes, suppress the levels of reactive oxygen species (ROS), and protect cancer cells from senescence. Melanoma cells, unlike melanocytes, are highly reliant on CDK4/6-mediated senescence suppression, which makes them particularly susceptible to CDK4/6 inhibition.

引用

页码：620 / 634

页数：15

共 36 条

[1] Molecular regulation of pancreatic β-cell mass development, maintenance, and expansion [J].

Ackermann, Amanda M. ;

Gannon, Maureen .

JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2007, 38 (1-2) :193-206

[2] 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

[3] 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

[4] E2F target genes: unraveling the biology [J].

Bracken, AP ;

Ciro, M ;

Cocito, A ;

Helin, K .

TRENDS IN BIOCHEMICAL SCIENCES, 2004, 29 (08) :409-417

[5] Proteome-scale purification of human proteins from bacteria [J].

Braun, P ;

Hu, YH ;

Shen, BH ;

Halleck, A ;

Koundinya, M ;

Harlow, E ;

LaBaer, J .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (05) :2654-2659

[6] Cellular senescence: when bad things happen to good cells [J].

Campisi, Judith ;

di Fagagna, Fabrizio d'Adda .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (09) :729-740

[7] Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure [J].

Dean, J. L. ;

Thangavel, C. ;

McClendon, A. K. ;

Reed, C. A. ;

Knudsen, E. S. .

ONCOGENE, 2010, 29 (28) :4018-4032

[8] FoxM1 is a downstream target and marker of HER2 overexpression in breast cancer [J].

Francis, Richard E. ;

Myatt, Stephen S. ;

Krol, Janna ;

Hartman, Johan ;

Peck, Barrie ;

McGovern, Ursula B. ;

Wang, Jun ;

Guest, Stephanie K. ;

Filipovic, Aleksandra ;

Gojis, Ondrej ;

Palmieri, Carlo ;

Peston, David ;

Shousha, Sami ;

Yu, Qunyan ;

Sicinski, Piotr ;

Coombes, R. Charles ;

Lam, Eric W. -F. .

INTERNATIONAL JOURNAL OF ONCOLOGY, 2009, 35 (01) :57-68

[9]

Fry DW, 2004, MOL CANCER THER, V3, P1427

[10] Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma [J].

Garraway, LA ;

Widlund, HR ;

Rubin, MA ;

Getz, G ;

Berger, AJ ;

Ramaswamy, S ;

Beroukhim, R ;

Milner, DA ;

Granter, SR ;

Du, JY ;

Lee, C ;

Wagner, SN ;

Li, C ;

Golub, TR ;

Rimm, DL ;

Meyerson, ML ;

Fisher, DE ;

Sellers, WR .

NATURE, 2005, 436 (7047) :117-122

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