Increased gene dosage of Ink4a/Arf results in cancer resistance and normal aging

被引：102
作者：
Matheu, A
Pantoja, C
Efeyan, A
Criado, LM
Martín-Caballero, J
Flores, JM
Klatt, P
Serrano, M [1 ]
机构：
[1] CNIO, E-28029 Madrid, Spain
[2] CSIC, CNB, Spanish Natl Ctr Biotechnol, E-28049 Madrid, Spain
[3] Univ Complutense Madrid, Dept Anim Surg & Med, E-28040 Madrid, Spain
来源：
GENES & DEVELOPMENT | 2004年 / 18卷 / 22期
关键词：
Ink4a; Arf; tumor suppression; stress; cancer resistance; aging; senescence;
D O I：
10.1101/gad.310304
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
Mammalian genes frequently present allelic variants that differ in their expression levels and that, in the case of tumor suppressor genes, can be of relevance for cancer susceptibility and aging. We report here the characterization of a novel mouse model with increased activity for the Ink4a and Arf tumor suppressors. We have generated a "super Ink4a/Arf" mouse strain carrying a transgenic copy of the entire Ink4a/Arf locus. Cells derived from super Ink4a/Arf mice have increased resistance to in vitro immortalization and oncogenic transformation. Importantly, super Ink4a/Arf mice manifest higher resistance to cancer compared to normal, nontransgenic, mice. Finally, super Ink4a/Arf mice have normal aging and lifespan. Together, these results indicate that modest increases in the activity of the Ink4a/Arf tumor suppressor result in a beneficial cancer-resistant phenotype without affecting normal viability or aging.
引用
收藏
页码：2736 / 2746
页数：11
相关论文
共 38 条
[1]   Cancer as a complex genetic trait: Tumor susceptibility in humans and mouse models [J].
Balmain, A .
CELL, 2002, 108 (02) :145-152
[2]   Cancer and ageing: Rival demons? [J].
Campisi, J .
NATURE REVIEWS CANCER, 2003, 3 (05) :339-349
[3]   As normal as normal can be? [J].
Carter, NP .
NATURE GENETICS, 2004, 36 (09) :931-932
[4]   E1A signaling to p53 involves the p19ARF tumor suppressor [J].
de Stanchina, E ;
McCurrach, ME ;
Zindy, F ;
Shieh, SY ;
Ferbeyre, G ;
Samuelson, AV ;
Prives, C ;
Roussel, MF ;
Sherr, CJ ;
Lowe, SW .
GENES & DEVELOPMENT, 1998, 12 (15) :2434-2442
[5]   'Super p53' mice exhibit enhanced DNA damage response, are tumor resistant and age normally [J].
García-Cao, I ;
García-Cao, M ;
Martín-Caballero, J ;
Criado, LM ;
Klatt, P ;
Flores, JM ;
Weill, JC ;
Blasco, MA ;
Serrano, M .
EMBO JOURNAL, 2002, 21 (22) :6225-6235
[6]   Detection of large-scale variation in the human genome [J].
Iafrate, AJ ;
Feuk, L ;
Rivera, MN ;
Listewnik, ML ;
Donahoe, PK ;
Qi, Y ;
Scherer, SW ;
Lee, C .
NATURE GENETICS, 2004, 36 (09) :949-951
[7]   Limited overlapping roles of p15INK4b and p18INK4c cell cycle inhibitors in proliferation and tumorigenesis [J].
Latres, E ;
Malumbres, M ;
Sotillo, R ;
Martín, J ;
Ortega, S ;
Martín-Caballero, J ;
Flores, JM ;
Cordón-Cardo, C ;
Barbacid, M .
EMBO JOURNAL, 2000, 19 (13) :3496-3506
[8]   Allelic variation in gene expression is common in the human genome [J].
Lo, HS ;
Wang, ZN ;
Hu, Y ;
Yang, HH ;
Gere, S ;
Buetow, KH ;
Lee, MP .
GENOME RESEARCH, 2003, 13 (08) :1855-1862
[9]   Tumor suppression by Ink4a-Arf:: progress and puzzles [J].
Lowe, SW ;
Sherr, CJ .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 2003, 13 (01) :77-83
[10]   Modulation of mammalian life span by the short isoform of p53 [J].
Maier, B ;
Gluba, W ;
Bernier, B ;
Turner, T ;
Mohammad, K ;
Guise, T ;
Sutherland, A ;
Thorner, M ;
Scrable, H .
GENES & DEVELOPMENT, 2004, 18 (03) :306-319
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