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Deficiency of the parathyroid hormone‐related peptide nuclear localization and carboxyl terminal sequences leads to premature skin ageing partially mediated by the upregulation of p27
Author(s) -
Jiang Minyue,
Chen Guangpei,
Lu Na,
Zhang Yongjie,
Jin Shulei,
Karaplis Andrew,
Goltzman David,
Miao Dengshun
Publication year - 2015
Publication title -
experimental dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.108
H-Index - 96
eISSN - 1600-0625
pISSN - 0906-6705
DOI - 10.1111/exd.12789
Subject(s) - downregulation and upregulation , endocrinology , apoptosis , medicine , parathyroid hormone related protein , ageing , chemistry , cyclin , premature aging , cell growth , knockout mouse , senescence , kinase , receptor , biology , cell cycle , calcium , parathyroid hormone , biochemistry , gene , physiology
We previously reported that deficiency of the PTH rP nuclear localization sequence ( NLS ) and C‐terminus in PTH rP knockin ( PTH rP KI ) mice resulted in premature ageing of skin. P27, a cyclin‐dependent kinase inhibitor, was upregulated in PTH rP KI mice and acted as a downstream target of the PTH rP NLS to regulate the proliferation of vascular smooth muscle cells. To determine the effects of p27 deficiency on premature skin ageing of PTH rP KI mice, we compared the skin phenotypes of PTH rP KI mice to those of p27 knockout (p27 −/− ) mice and to those of double homozygous p27‐deficient and PTH rP KI (p27 −/− PTH rP KI ) mice at 2 weeks age. Compared with wild‐type littermates, PTH rP KI mice displayed thinner skin and decreased subcutaneous fat and collagen fibres, decreased skin cell proliferation and increased apoptosis, higher expression of p27, p19 and p53 and lower expression of cyclin E and CDK 2, and increased reactive oxygen species levels and decreased antioxidant capacity. Deficiency of p27 in the PTH rP KI mice at least in part corrected the skin premature ageing phenotype resulting in thicker skin and increased subcutaneous fat and collagen. These alternations were associated with higher expression of CDK 2 and cyclin E, lower expression of p19 and p53, and enhanced antioxidant capacity with increased skin cell proliferation and inhibition of apoptosis. Our results indicate that the NLS and C‐terminus of PTH rP play a critical role in preventing skin from premature ageing that is partially mediated by p27.