Proline dehydrogenase promotes senescence through the generation of reactive oxygen species

• Published in: Journal of cell science Vol. 130; no. 8; pp. 1413 - 1420
• Main Authors: Nagano, Taiki, Nakashima, Akio, Onishi, Kengo, Kawai, Kosuke, Awai, Yuto, Kinugasa, Mizuki, Iwasaki, Tetsushi, Kikkawa, Ushio, Kamada, Shinji
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15.04.2017
• Subjects: Acetylcysteine - pharmacology; Age; Amino acids; Cell Line; Cellular Senescence - drug effects; Cellular Senescence - genetics; Cellular stress response; Damage accumulation; Damage prevention; Dehydrogenase; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; DNA Damage - genetics; Ectopic expression; Fibroblasts - drug effects; Fibroblasts - physiology; Furans - pharmacology; Gene expression; Humans; Metabolism; N-Acetyl-L-cysteine; p53 Protein; Pharmacology; Proline; Proline dehydrogenase; Proline Oxidase - genetics; Proline Oxidase - metabolism; Reactive oxygen species; Reactive Oxygen Species - metabolism; RNA, Small Interfering - genetics; Senescence; Transcription; Transgenes - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Reactive oxygen species; Senescence; PRODH; Amino acid metabolism; p53
• ISSN: 0021-9533; 1477-9137
• DOI: 10.1242/jcs.196469

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 by ) 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 ( ) 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.