DeltaNp63alpha overexpression induces downregulation of Sirt1 and an accelerated aging phenotype in the mouse.
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.
Sommer
Matthias
M
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
Poliak
Nina
N
Upadhyay
Sunil
S
Ratovitski
Edward
E
Nelkin
Barry D
BD
Donehower
Lawrence A
LA
Sidransky
David
D
D000818:Animals; D049109:Cell Proliferation; D016922:Cellular Senescence; D020405:Dermis / Q000473:pathology; D015536:Down-Regulation; D016158:Genes, p53; D006801:Humans; D008136:Longevity; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000378:metabolism*; D012867:Skin / Q000378:metabolism / Q000473:pathology; D015595:Skin Aging; D012871:Skin Diseases / Q000235:genetics / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins