Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin
Department of Cell Biology; Department of Cancer Biology
Cell Aging; Epidermis; Proto-Oncogene Proteins c-mdm2; Signal Transduction; Skin Aging; Stem Cells; Tumor Suppressor Protein p53
Cancer Biology | Cell Biology
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.
DOI of Published Version
Dev Biol. 2011 May 1;353(1):1-9. Epub 2011 Feb 17. Link to article on publisher's site
Gannon, Hugh S.; Donehower, Lawrence A.; Lyle, Stephen; and Jones, Stephen N., "Mdm2-p53 signaling regulates epidermal stem cell senescence and premature aging phenotypes in mouse skin" (2011). Cell and Developmental Biology Publications. 97.