Sommer Matthias, Poliak Nina, Upadhyay Sunil, Ratovitski Edward, Nelkin Barry D, Donehower Lawrence A, Sidransky David
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Cell Cycle. 2006 Sep;5(17):2005-11. doi: 10.4161/cc.5.17.3194. Epub 2006 Sep 1.
p63 is highly expressed in the skin and appears to be an early marker of keratinocyte differentiation. To examine the role of p63 in vivo, we generated transgenic mice that overexpress deltaNp63alpha in the skin. These mice exhibited an accelerated aging phenotype in the skin characterized by striking wound healing defects, decreased skin thickness, decreased subcutaneous fat tissue, hair loss, and decreased cell proliferation. The accelerated skin aging was accompanied by a dramatic decrease in longevity of the mice. We found that aging in deltaNp63alpha transgenic mice and other mouse models correlated with levels of Sirt1, a mammalian SIR2 orthologue thought to extend the lifespan in lower species. Moreover, increased deltaNp63alpha expression induced cellular senescence that was rescued by Sirt1. Our data suggest that deltaNp63alpha levels may affect aging in mammals, at least in part, through regulation of Sirt1.
p63在皮肤中高度表达，似乎是角质形成细胞分化的早期标志物。为了研究p63在体内的作用，我们构建了在皮肤中过表达ΔNp63α的转基因小鼠。这些小鼠在皮肤中表现出加速衰老的表型，其特征为明显的伤口愈合缺陷、皮肤厚度降低、皮下脂肪组织减少、脱发以及细胞增殖减少。皮肤加速衰老伴随着小鼠寿命的显著缩短。我们发现，ΔNp63α转基因小鼠和其他小鼠模型中的衰老与Sirt1水平相关，Sirt1是一种哺乳动物SIR2同源物，被认为可延长低等物种的寿命。此外，ΔNp63α表达增加诱导细胞衰老，而Sirt1可挽救这种衰老。我们的数据表明，ΔNp63α水平可能至少部分地通过调节Sirt1来影响哺乳动物的衰老。
