title: Ligand-activated PPARδ inhibits UVB-induced senescence of human keratinocytes via PTEN-mediated inhibition of superoxide production.
abstract: UV radiation-mediated photodamage to the skin has been implicated in premature aging and photoaging-related skin cancer and melanoma. Little is known about the cellular events that underlie premature senescence, or how to impede these events. In the present study we demonstrate that PPARδ (peroxisome-proliferator-activated receptor δ) regulates UVB-induced premature senescence of normal keratinocytes. Activation of PPARδ by GW501516, a specific ligand of PPARδ, significantly attenuated UVB-mediated generation of ROS (reactive oxygen species) and suppressed senescence of human keratinocytes. Ligand-activated PPARδ up-regulated the expression of PTEN (phosphatase and tensin homologue deleted on chromosome 10) and suppressed the PI3K (phosphatidylinositol 3-kinase)/Akt pathway. Concomitantly, translocation of Rac1 to the plasma membrane, which leads to the activation of NADPH oxidases and generation of ROS, was significantly attenuated. siRNA (small interfering RNA)-mediated knockdown of PTEN abrogated the effects of PPARδ on cellular senescence, on PI3K/Akt/Rac1 signalling and on generation of ROS in keratinocytes exposed to UVB. Finally, when HR-1 hairless mice were treated with GW501516 before exposure to UVB, the number of senescent cells in the skin was significantly reduced. Thus ligand-activated PPARδ confers resistance to UVB-induced cellular senescence by up-regulating PTEN and thereby modulating PI3K/Akt/Rac1 signalling to reduce ROS generation in keratinocytes.
authors.affiliation: Department of Animal Biotechnology, Konkuk University, Gwangjin-Gu, Seoul, Republic of Korea.
authors.forename: Sun Ah
authors.initials: SA
authors.lastname: Ham
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Hwang
authors.forename: Taesik
authors.initials: T
authors.lastname: Yoo
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Eun Sil
authors.initials: ES
authors.lastname: Kang
authors.forename: Chankyu
authors.initials: C
authors.lastname: Park
authors.forename: Jae-Wook
authors.initials: JW
authors.lastname: Oh
authors.forename: Hoon Taek
authors.initials: HT
authors.lastname: Lee
authors.forename: Gyesik
authors.initials: G
authors.lastname: Min
authors.forename: Jin-Hoi
authors.initials: JH
authors.lastname: Kim
authors.forename: Han Geuk
authors.initials: HG
authors.lastname: Seo
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence; D002648:Child; D004789:Enzyme Activation; D006801:Humans; D015603:Keratinocytes / Q000502:physiology / Q000528:radiation effects*; D008024:Ligands; D051379:Mice; D008812:Mice, Hairless; D047494:PPAR delta / Q000819:agonists / Q000502:physiology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D013481:Superoxides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D014466:Ultraviolet Rays; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: C425931:GW 501516; D008024:Ligands; D047494:PPAR delta; D013844:Thiazoles; D013481:Superoxides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; D020830:rac1 GTP-Binding Protein