期刊
CELL DEATH AND DIFFERENTIATION
卷 17, 期 6, 页码 1025-1033出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.204
关键词
embryonic stem cell; self-renewal; differentiation; Nanog; oct4 repression; nitric oxide
资金
- Direccion General de Investigacion Cientifica y Tecnica [SAF2007/60105, CYT-836, SAF2005-08014, SAF2003-03307, SAF2006-06673]
- Instituto de Salud Carlos III [TERCEL RD06/0010/0025, RCMN C03/08, RETIC RD06/0015/0013, CIBERDEM]
- Junta de Andalucia [CTS576, 0009/06]
- Fondo de Investigaciones Sanitarias [FIS-052106]
- Consejeria de Salud-Junta de Andalucia [PI-0095/2007]
Exposure of mouse embryonic stem (mES) cells to high concentrations of chemical nitric oxide (NO) donors promotes differentiation, but the mechanisms involved in this process at the gene expression level are poorly defined. In this study we report that culture of mES cells in the presence of 0.25-1.0mM diethylenetriamine nitric oxide adduct (DETA-NO) leads to downregulation of Nanog and Oct4, the two master genes involved in the control of the pluripotent state. This action of NO was also apparent in the human ES cell line, HS 181. The suppressive action of NO on Nanog gene depends on the activation of p53 repressor protein by covalent modifications, such as pSer15, pSer315, pSer392 and acetyl Lys 379. NO-induced repression of Nanog is also associated with binding of trimethylated histone H3 and pSer315 p53 to its promoter region. In addition, exposure to 0.5mM DETA-NO induces early differentiation events of cells with acquisition of epithelial morphology and expression of markers of definitive endoderm, such as FoxA2, Gata4, Hfn1-b and Sox 17. This phenotype was increased when cells were treated with valproic acid (VPA) for 10 days. Cell Death and Differentiation (2010) 17, 1025-1033; doi: 10.1038/cdd.2009.204; published online 15 January 2010
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