A Sleeping Beauty mutagenesis screen reveals a tumor suppressor role for Ncoa2/Src-2 in liver cancer

被引：92
作者：
O'Donnell, Kathryn A. [1 ,5 ]
Keng, Vincent W. [6 ,7 ,8 ]
York, Brian [9 ]
Reineke, Erin L. [9 ]
Seo, Daekwan [10 ]
Fan, Danhua [6 ]
Silverstein, Kevin A. T. [6 ]
Schrum, Christina T. [1 ,5 ]
Xie, Wei Rose [1 ,5 ]
Mularoni, Loris [2 ,3 ]
Wheelan, Sarah J. [2 ,3 ]
Torbenson, Michael S. [4 ]
O'Malley, Bert W. [9 ]
Largaespada, David A. [6 ,7 ,8 ]
Boeke, Jef D. [1 ,5 ]
机构：
[1] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA
[2] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA
[3] Johns Hopkins Univ, Sch Med, Div Biostat & Bioinformat, Baltimore, MD 21205 USA
[4] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA
[5] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA
[6] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA
[7] Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA
[8] Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA
[9] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[10] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
来源：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 21期
基金：
美国国家卫生研究院;
关键词：
cancer gene identification; mouse models of cancer; Myc oncogene; hepatocellular carcinoma; TRANSPOSON MUTAGENESIS; GENE DISCOVERY; ZFX CONTROLS; MYC; PROTEIN; CATENIN; PROLIFERATION; DYSTROBREVIN; INHIBITION; CARCINOMAS;
D O I：
10.1073/pnas.1115433109
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：
07 ; 0710 ; 09 ;
摘要：
The Sleeping Beauty (SB) transposon mutagenesis system is a powerful tool that facilitates the discovery of mutations that accelerate tumorigenesis. In this study, we sought to identify mutations that cooperate with MYC, one of the most commonly dysregulated genes in human malignancy. We performed a forward genetic screen with a mouse model of MYC-induced liver cancer using SB-mediated mutagenesis. We sequenced insertions in 63 liver tumor nodules and identified at least 16 genes/loci that contribute to accelerated tumor development. RNAi-mediated knockdown in a liver progenitor cell line further validate three of these genes, Ncoa2/Src-2, Zfx, and Dtnb, as tumor suppressors in liver cancer. Moreover, deletion of Ncoa2/Src-2 in mice predisposes to diethylnitrosamine-induced liver tumorigenesis. These findings reveal genes and pathways that functionally restrain MYC-mediated liver tumorigenesis and therefore may provide targets for cancer therapy.
引用
收藏
页码：E1377 / E1386
页数：10
相关论文
共 59 条
  • [1] Transcription factor Zfx controls BCR-induced proliferation and survival of B lymphocytes
    Arenzana, Teresita L.
    Smith-Raska, Matthew R.
    Reizis, Boris
    [J]. BLOOD, 2009, 113 (23) : 5857 - 5867
  • [2] Developmental context determines latency of MYC-induced tumorigenesis
    Beer, S
    Zetterberg, A
    Ihrie, RA
    McTaggart, RA
    Yang, QW
    Bradon, N
    Arvanitis, C
    Attardi, LD
    Feng, S
    Ruebner, B
    Cardiff, RD
    Felsher, DW
    [J]. PLOS BIOLOGY, 2004, 2 (11) : 1785 - 1798
  • [3] Buendia MA, 2000, SEMIN CANCER BIOL, V10, P185
  • [4] α-T-catenin is expressed in human brain and interacts with the Wnt signaling pathway but is not responsible for linkage to chromosome 10 in Alzheimer's disease
    Busby, V
    Goossens, S
    Nowotny, P
    Hamilton, G
    Smemo, S
    Harold, D
    Turic, D
    Jehu, L
    Myers, A
    Womick, M
    Woo, D
    Compton, D
    Doil, LM
    Tacey, KM
    Lau, KF
    Al-Saraj, S
    Killick, R
    Pickering-Brown, S
    Moore, P
    Hollingworth, P
    Archer, N
    Foy, C
    Walter, S
    Lendon, C
    Iwatsubo, T
    Morris, JC
    Norton, J
    Mann, D
    Janssens, B
    Hardy, J
    O'Donovan, M
    Jones, L
    Williams, J
    Holmans, P
    Owen, MJ
    Grupe, A
    Powell, J
    van Hengel, J
    Goate, A
    Van Roy, F
    Lovestone, S
    [J]. NEUROMOLECULAR MEDICINE, 2004, 5 (02) : 133 - 146
  • [5] Carlson CM, 2003, GENETICS, V165, P243
  • [6] Association of dystrobrevin and regulatory subunit of protein kinase A: A new role for dystrobrevin as a scaffold for signaling proteins
    Ceccarini, Marina
    Grasso, Margherita
    Veroni, Caterina
    Gambara, Guido
    Artegiani, Benedetta
    Macchia, Gianfranco
    Ramoni, Carlo
    Torreri, Paola
    Mallozzi, Cinzia
    Petrucci, Tamara C.
    Macioce, Pompeo
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 2007, 371 (05) : 1174 - 1187
  • [7] Absence of the SRC-2 Coactivator Results in a Glycogenopathy Resembling Von Gierke's Disease
    Chopra, Atul R.
    Louet, Jean-Francois
    Saha, Pradip
    An, Jie
    DeMayo, Franco
    Xu, Jianming
    York, Brian
    Karpen, Saul
    Finegold, Milton
    Moore, David
    Chan, Lawrence
    Newgard, Christopher B.
    O'Malley, Bert W.
    [J]. SCIENCE, 2008, 322 (5906) : 1395 - 1399
  • [8] Chou Janice Yang, 2002, Current Molecular Medicine (Hilversum), V2, P121, DOI 10.2174/1566524024605798
  • [9] Whole-Body Sleeping Beauty Mutagenesis Can Cause Penetrant Leukemia/Lymphoma and Rare High-Grade Glioma without Associated Embryonic Lethality
    Collier, Lara S.
    Adams, David J.
    Hackett, Christopher S.
    Bendzick, Laura E.
    Akagi, Keiko
    Davies, Michael N.
    Diers, Miechaleen D.
    Rodriguez, Fausto J.
    Bender, Aaron M.
    Tieu, Christina
    Matise, Ilze
    Dupuy, Adam J.
    Copeland, Neal G.
    Jenkins, Nancy A.
    Hodgson, J. Graeme
    Weiss, William A.
    Jenkins, Robert B.
    Largaespada, David A.
    [J]. CANCER RESEARCH, 2009, 69 (21) : 8429 - 8437
  • [10] Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse
    Collier, LS
    Carlson, CM
    Ravimohan, S
    Dupuy, AJ
    Largaespada, DA
    [J]. NATURE, 2005, 436 (7048) : 272 - 276
123456