Cyclin-Dependent Kinase Inhibitor p21 Controls Adult Neural Stem Cell Expansion by Regulating Sox2 Gene Expression

被引：163

作者：

Angeles Marques-Torrejon, M. ^{[1
,2
]}

Porlan, Eva ^{[1
,2
]}

Banito, Ana ^{[3
]}

Gomez-Ibarlucea, Esther ^{[4
,5
]}

Lopez-Contreras, Andres J. ^{[6
]}

Fernandez-Capetillo, Oscar ^{[6
]}

Vidal, Anxo ^{[4
,5
]}

Gil, Jesus ^{[3
]}

Torres, Josema ^{[1
]}

Farinas, Isabel ^{[1
,2
]}

机构：

[1] Univ Valencia, Dept Biol Celular, E-46100 Valencia, Spain

[2] Univ Valencia, Ctr Invest Biomed Red Enfermedades Neurodegenerat, E-46100 Valencia, Spain

[3] Univ London Imperial Coll Sci Technol & Med, Cell Proliferat Grp, MRC Clin Sci Ctr, Fac Med, London W12 0NN, England

[4] Univ Santiago de Compostela, Dept Fisiol, Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela 15782, Spain

[5] Univ Santiago de Compostela, Ctr Invest Med Mol CIMUS, Inst Invest Sanitaria Santiago IDIS, Santiago De Compostela 15782, Spain

[6] Spanish Natl Canc Res Ctr CNIO, Genom Instabil Grp, Madrid 28029, Spain

来源：

CELL STEM CELL | 2013年 / 12卷 / 01期

基金：

英国医学研究理事会; 欧洲研究理事会;

关键词：

ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE; SELF-RENEWAL; REPLICATIVE STRESS; COPY NUMBER; PROLIFERATION; ATR; P53; DIFFERENTIATION; P21(WAF1/CIP1);

D O I：

10.1016/j.stem.2012.12.001

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

In the adult brain, continual neurogenesis of olfactory neurons is sustained by the existence of neural stem cells (NSCs) in the subependymal niche. Elimination of the cyclin-dependent kinase inhibitor 1A (p21) leads to premature exhaustion of the subependymal NSC pool, suggesting a relationship between cell cycle control and long-term self-renewal, but the molecular mechanisms underlying NSC maintenance by p21 remain unexplored. Here we identify a function of p21 in the direct regulation of the expression of pluripotency factor Sox2, a key regulator of the specification and maintenance of neural progenitors. We observe that p21 directly binds a Sox2 enhancer and negatively regulates Sox2 expression in NSCs. Augmented levels of Sox2 in p21 null cells induce replicative stress and a DNA damage response that leads to cell growth arrest mediated by increased levels of p19(Arf) and p53. Our results show a regulation of NSC expansion driven by a p21/Sox2/p53 axis.

引用

页码：88 / 100

页数：13

共 55 条

[41] A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging [J].