title: Proline dehydrogenase promotes senescence through the generation of reactive oxygen species.
abstract: Cellular senescence is a complex stress response characterized by permanent loss of proliferative capacity and is implicated in age-related disorders. Although the transcriptional activity of p53 (encoded byTP53) is known to be vital for senescence induction, the downstream effector genes critical for senescence remain unsolved. Recently, we have identified the proline dehydrogenase gene (PRODH) to be upregulated specifically in senescent cells in a p53-dependent manner, and the functional relevance of this to senescence is yet to be defined. Here, we conducted functional analyses to explore the relationship between PRODH and the senescence program. We found that genetic and pharmacological inhibition of PRODH suppressed senescent phenotypes induced by DNA damage. Furthermore, ectopic expression of wild-type PRODH, but not enzymatically inactive forms, induced senescence associated with the increase in reactive oxygen species (ROS) and the accumulation of DNA damage. Treatment with N-acetyl-L-cysteine, a ROS scavenger, prevented senescence induced by PRODH overexpression. These results indicate that PRODH plays a causative role in DNA damage-induced senescence through the enzymatic generation of ROS.
authors.affiliation: Division of Signal Pathways, Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.|Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Taiki
authors.initials: T
authors.lastname: Nagano
authors.affiliation: Division of Signal Functions, Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.|Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Nakashima
authors.affiliation: Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Onishi
authors.affiliation: Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kawai
authors.affiliation: Department of Biology, Faculty of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Awai
authors.affiliation: Department of Biology, Faculty of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Mizuki
authors.initials: M
authors.lastname: Kinugasa
authors.affiliation: Division of Signal Pathways, Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.|Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.|Department of Biology, Faculty of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Iwasaki
authors.affiliation: Division of Signal Functions, Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.|Department of Bioresource Science, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Ushio
authors.initials: U
authors.lastname: Kikkawa
authors.affiliation: Division of Signal Pathways, Biosignal Research Center, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan skamada@kobe-u.ac.jp.|Department of Biology, Graduate School of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.|Department of Biology, Faculty of Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan.
authors.forename: Shinji
authors.identifier: 0000-0003-0658-1785
authors.initials: S
authors.lastname: Kamada
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002460:Cell Line; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D005663:Furans / Q000494:pharmacology; D006801:Humans; D011394:Proline Oxidase / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D005663:Furans; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D011394:Proline Oxidase; D000111:Acetylcysteine; C018675:tetrahydrofurfuryl alcohol
keywords: Amino acid metabolism; PRODH; Reactive oxygen species; Senescence; p53