Fibroblast growth factor type 2 signaling is critical for DNA repair in human keratinocyte stem cells.
Fibroblast growth factor type 2 signaling is critical for DNA repair in human keratinocyte stem cells.
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DOI：
10.1002/stem.485
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发表时间：
2010-09
期刊：
影响因子：
5.2
通讯作者：
Martin, Michele T.
中科院分区：
文献类型：
--
作者：
Harfouche, Ghida;Vaigot, Pierre;Rachidi, Walid;Rigaud, Odile;Moratille, Sandra;Marie, Melanie;Lemaitre, Gilles;Fortunel, Nicolas O.;Martin, Michele T.
组织干细胞必须具有上级维持和修复系统，以确保多代基因组的稳定性，这在分化程度更高的细胞中不太必要。我们之前报道过，人类角质形成细胞干细胞比其直系后代角质形成细胞祖细胞对电离辐射毒性的抵抗力更强。在本研究中，我们解决了这种差异的机制。DNA修复的研究表明，单和双DNA链断裂的修复更迅速，更有效地在干细胞比在祖细胞。由于细胞信号传导是DNA损伤管理中的关键调控步骤，因此进行了基因分析研究。数据显示，成纤维细胞生长因子2型（FGF 2）信号通路的几个基因在干细胞中而不是在祖细胞中被DNA损伤诱导。此外，在辐射的干细胞中发现FGF 2蛋白的含量增加，无论是分泌型还是细胞型蛋白。为了检查内源性FGF 2在DNA修复中的作用，将干细胞暴露于FGF 2途径抑制剂。阻断FGF 2受体（FGF受体1）或激酶（Ras-促分裂原活化蛋白激酶1）导致角质形成细胞干细胞中单链和双链DNA断裂修复的抑制。此外，用外源性FGF 2补充祖细胞激活了它们的DNA修复。我们认为，除了众所周知的强有丝分裂原和促生存因子的作用外，FGF 2还通过激活应激诱导的DNA修复来帮助维持干细胞基因组的完整性。干细胞2010; 28：1639-1648.
Tissue stem cells must be endowed with superior maintenance and repair systems to ensure genomic stability over multiple generations, which would be less necessary in more differentiated cells. We previously reported that human keratinocyte stem cells were more resistant to ionizing radiation toxicity than their direct progeny, the keratinocyte progenitor cells. In the present study we addressed the mechanisms underlying this difference. Investigations of DNA repair showed that both single and double DNA strand breaks were repaired more rapidly and more efficiently in stem cells than in progenitors. As cell signaling is a key regulatory step in the management of DNA damage, a gene profiling study was performed. Data revealed that several genes of the fibroblast growth factor type 2 (FGF2) signaling pathway were induced by DNA damage in stem cells and not in progenitors. Furthermore, an increased content of the FGF2 protein was found in irradiated stem cells, both for the secreted and the cellular forms of the protein. To examine the role of endogenous FGF2 in DNA repair, stem cells were exposed to FGF2 pathway inhibitors. Blocking the FGF2 receptor (FGF receptor 1) or the kinase (Ras-mitogen-activated protein kinase 1) resulted in a inhibition of single and double DNA strand-break repair in the keratinocyte stem cells. Moreover, supplementing the progenitor cells with exogenous FGF2 activated their DNA repair. We propose that, apart from its well-known role as a strong mitogen and prosurvival factor, FGF2 helps to maintain genomic integrity in stem cells by activating stress-induced DNA repair. Stem Cells 2010; 28:1639–1648.
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DOI：
10.1016/j.mrrev.2010.01.007
发表时间：
2010-04-01
影响因子：
5.3
作者：
Harfouche, Ghida;Martin, Michele T.
通讯作者：
Martin, Michele T.
影响因子：
14.8
作者：
Olive, Peggy L.;Banath, Judit P.
通讯作者：
Banath, Judit P.
影响因子：
5.2
作者：
Bithell, Angela;Finch, Sophie E.;Williams, Brenda P.
通讯作者：
Williams, Brenda P.
影响因子：
3.3
作者：
Mudo, G.;Bonomo, A.;Belluardo, Natale
通讯作者：
Belluardo, Natale
影响因子：
5.7
作者：
Klokov, Dmitry;MacPhail, Susan M.;Olive, Peggy L.
通讯作者：
Olive, Peggy L.