Global loss of imprinting leads to widespread tumorigenesis in adult mice

被引:202
作者
Holm, TM
Jackson-Grusby, L
Brambrink, T
Yamada, Y
Rideout, WM
Jaenisch, R [1 ]
机构
[1] Whitehead Inst Biomed Res, Cambridge, MA 02142 USA
[2] MIT, Cambridge, MA 02142 USA
关键词
D O I
10.1016/j.ccr.2005.09.007
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Loss of imprinting (LOI), commonly observed in human tumors, refers to loss of monoallelic gene regulation normally conferred by parent-of-origin-specific DNA methylation. To test the function of LOI in tumorigenesis, we developed a model by using transient demethylation to generate imprint-free mouse embryonic stem cells (IF-ES cells). Embryonic fibroblasts derived from IF-ES cells (IF-MEFs) display TGF beta resistance and reduced p19 and p53 expression and form tumors in SCID mice. IF-MEFs exhibit spontaneous immortalization and cooperate with H-Ras in cellular transformation. Chimeric animals derived from IF-ES cells develop multiple tumors arising from the injected IF-ES cells within 12 months. These data demonstrate that LOI alone can predispose cells to tumorigenesis and identify a pathway through which immortality conferred by LOI lowers the threshold for transformation.
引用
收藏
页码:275 / 285
页数:11
相关论文
共 59 条
  • [1] Growth restricted in vitro culture conditions alter the imprinted gene expression patterns of mouse embryonic stem cells
    Baqir, S
    Smith, LC
    [J]. CLONING AND STEM CELLS, 2003, 5 (03) : 199 - 212
  • [2] Bartolomei MS, 2002, ADV EXP MED BIOL, V518, P239
  • [3] Altered methylation patterns in cancer cell genomes: Cause or consequence?
    Baylin, S
    Bestor, TH
    [J]. CANCER CELL, 2002, 1 (04) : 299 - 305
  • [4] Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality
    Biniszkiewicz, D
    Gribnau, J
    Ramsahoye, B
    Gaudet, F
    Eggan, K
    Humpherys, D
    Mastrangelo, MA
    Jun, Z
    Walter, J
    Jaenisch, R
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 2002, 22 (07) : 2124 - 2135
  • [5] Bypass of senescence after disruption of p21(CIP1/WAF1) gene in normal diploid human fibroblasts
    Brown, JP
    Wei, WY
    Sedivy, JM
    [J]. SCIENCE, 1997, 277 (5327) : 831 - 834
  • [6] p21 Is a critical CDK2 regulator essential for proliferation control in Rb-deficient cells
    Brugarolas, J
    Bronson, RT
    Jacks, T
    [J]. JOURNAL OF CELL BIOLOGY, 1998, 141 (02) : 503 - 514
  • [7] Improved properties of FLP recombinase evolved by cycling mutagenesis
    Buchholz, F
    Angrand, PO
    Stewart, AF
    [J]. NATURE BIOTECHNOLOGY, 1998, 16 (07) : 657 - 662
  • [8] DNA hypomethylation leads to elevated mutation rates
    Chen, RZ
    Pettersson, U
    Beard, C
    Jackson-Grusby, L
    Jaenisch, R
    [J]. NATURE, 1998, 395 (6697) : 89 - 93
  • [9] Links between tumor suppressors:: p53 is required for TGF-β gene responses by cooperating with Smads
    Cordenonsi, M
    Dupont, S
    Maretto, S
    Insinga, A
    Imbriano, C
    Piccolo, S
    [J]. CELL, 2003, 113 (03) : 301 - 314
  • [10] Loss of IGF2 imprinting:: A potential marker of colorectal cancer risk
    Cui, HM
    Cruz-Correa, M
    Giardiello, FM
    Hutcheon, DF
    Kafonek, DR
    Brandenburg, S
    Wu, YQ
    He, XB
    Powe, NR
    Feinberg, AP
    [J]. SCIENCE, 2003, 299 (5613) : 1753 - 1755