Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin.
Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin.
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DOI：
10.1016/j.ydbio.2011.02.007
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发表时间：
2011-05-01
影响因子：
2.7
通讯作者：
Jones SN
中科院分区：
文献类型：
--
作者：
Gannon HS;Donehower LA;Lyle S;Jones SN
p53转录因子被各种类型的细胞应激或DNA损伤激活，诱导控制细胞生长和抑制肿瘤形成的基因表达。对表达p53突变形式的小鼠的分析表明，不适当的p53激活可以改变组织稳态和寿命，将p53肿瘤抑制功能与加速衰老联系起来。然而，其他在各种组织中显示野生型p53水平升高的小鼠模型未能证实p53与衰老表型之间的联系，这可能是由于在这些模型中保留了负调节p53活性的信号通路。在本研究中，我们培育了表皮缺乏Mdm2的小鼠。Mdm2 （p53的主要负调节因子）的缺失导致小鼠皮肤出现衰老表型，包括表皮变薄、伤口愈合减少和毛皮逐渐脱落。这些表型是由于p53介导的表皮干细胞衰老和表皮干细胞功能的逐渐丧失而引起的。这些结果表明，通过消融Mdm2激活内源性p53可以诱导小鼠加速衰老表型。
The p53 transcription factor is activated by various types of cell stress or DNA damage, and induces the expression of genes that control cell growth and inhibit tumor formation. Analysis of mice that express mutant forms of p53 suggest that inappropriate p53 activation can alter tissue homeostasis and life span, connecting p53 tumor suppressor functions with accelerated aging. However, other mouse models that display increased levels of wildtype p53 in various tissues fail to corroborate a link between p53 and aging phenotypes, possibly due to the retention of signaling pathways that negatively regulate p53 activity in these models. In this present study, we have generated mice lacking Mdm2 in the epidermis. Deletion of Mdm2, the chief negative regulator of p53, induced an aging phenotype in the skin of mice, including thinning of the epidermis, reduced wound healing, and a progressive loss of fur. These phenotypes arise due to an induction of p53-mediated senescence in epidermal stem cells and a gradual loss of epidermal stem cell function. These results reveal that activation of endogenous p53 by ablation of Mdm2 can induce accelerated aging phenotypes in mice.
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DOI：
10.1007/978-1-59745-060-7_14
发表时间：
2009
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
6.5
作者：
Morris, RJ;Potten, CS
通讯作者：
Potten, CS
影响因子：
10.5
作者：
Maier, B;Gluba, W;Scrable, H
通讯作者：
Scrable, H
影响因子：
3.7
作者：
Flores I;Blasco MA
通讯作者：
Blasco MA