title: 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.
abstract: We previously reported that deficiency of the PTHrP nuclear localization sequence (NLS) and C-terminus in PTHrP knockin (PTHrP KI) mice resulted in premature ageing of skin. P27, a cyclin-dependent kinase inhibitor, was upregulated in PTHrP KI mice and acted as a downstream target of the PTHrP NLS to regulate the proliferation of vascular smooth muscle cells. To determine the effects of p27 deficiency on premature skin ageing of PTHrP KI mice, we compared the skin phenotypes of PTHrP KI mice to those of p27 knockout (p27(-/-) ) mice and to those of double homozygous p27-deficient and PTHrP KI (p27(-/-) PTHrP KI) mice at 2 weeks age. Compared with wild-type littermates, PTHrP 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 CDK2, and increased reactive oxygen species levels and decreased antioxidant capacity. Deficiency of p27 in the PTHrP 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 CDK2 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 PTHrP play a critical role in preventing skin from premature ageing that is partially mediated by p27.
authors.affiliation: Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Minyue
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Guangpei
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Na
authors.initials: N
authors.lastname: Lu
authors.affiliation: Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Shulei
authors.initials: S
authors.lastname: Jin
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Karaplis
authors.affiliation: Calcium Research Laboratory, McGill University Health Centre and Department of Medicine, McGill University, Montreal, QC, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: Department of Anatomy, Histology and Embryology, State Key Laboratory of Reproductive Medicine, The Research Center for Bone and Stem Cells, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D018345:Mice, Knockout; D008819:Mice, Nude; D019913:Nuclear Localization Signals; D044162:Parathyroid Hormone-Related Protein / Q000172:deficiency* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015595:Skin Aging / Q000473:pathology / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D019913:Nuclear Localization Signals; D044162:Parathyroid Hormone-Related Protein; D017382:Reactive Oxygen Species; D050760:Cyclin-Dependent Kinase Inhibitor p27
keywords: nuclear localization sequence; oxidative stress; p27; parathyroid hormone-related peptide; skin ageing