{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T06:09:40Z","timestamp":1782886180174,"version":"3.54.5"},"reference-count":41,"publisher":"The Company of Biologists","issue":"8","license":[{"start":{"date-parts":[[2017,10,15]],"date-time":"2017-10-15T00:00:00Z","timestamp":1508025600000},"content-version":"vor","delay-in-days":183,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["25640063"],"award-info":[{"award-number":["25640063"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,4,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>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 TP53) 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.<\/jats:p>","DOI":"10.1242\/jcs.196469","type":"journal-article","created":{"date-parts":[[2017,3,7]],"date-time":"2017-03-07T01:10:28Z","timestamp":1488849028000},"page":"1413-1420","source":"Crossref","is-referenced-by-count":53,"title":["Proline dehydrogenase promotes senescence through the generation of reactive oxygen species"],"prefix":"10.1242","volume":"130","author":[{"given":"Taiki","family":"Nagano","sequence":"first","affiliation":[{"name":"Division of Signal Pathways, Biosignal Research Center, Kobe University 1 , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"},{"name":"Graduate School of Science, Kobe University 2 Department of Biology , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akio","family":"Nakashima","sequence":"additional","affiliation":[{"name":"Kobe University, 1-1 Rokkodai-cho 3 Division of Signal Functions, Biosignal Research Center , , Nada-ku, Kobe 657-8501 , Japan"},{"name":"Graduate School of Agricultural Science, Kobe University 4 Department of Bioresource Science , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Onishi","sequence":"additional","affiliation":[{"name":"Graduate School of Science, Kobe University 2 Department of Biology , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Kawai","sequence":"additional","affiliation":[{"name":"Graduate School of Science, Kobe University 2 Department of Biology , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuto","family":"Awai","sequence":"additional","affiliation":[{"name":"Kobe University 5 Department of Biology, Faculty of Science , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuki","family":"Kinugasa","sequence":"additional","affiliation":[{"name":"Kobe University 5 Department of Biology, Faculty of Science , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsushi","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Division of Signal Pathways, Biosignal Research Center, Kobe University 1 , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"},{"name":"Graduate School of Science, Kobe University 2 Department of Biology , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"},{"name":"Kobe University 5 Department of Biology, Faculty of Science , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ushio","family":"Kikkawa","sequence":"additional","affiliation":[{"name":"Kobe University, 1-1 Rokkodai-cho 3 Division of Signal Functions, Biosignal Research Center , , Nada-ku, Kobe 657-8501 , Japan"},{"name":"Graduate School of Agricultural Science, Kobe University 4 Department of Bioresource Science , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0658-1785","authenticated-orcid":false,"given":"Shinji","family":"Kamada","sequence":"additional","affiliation":[{"name":"Division of Signal Pathways, Biosignal Research Center, Kobe University 1 , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"},{"name":"Graduate School of Science, Kobe University 2 Department of Biology , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"},{"name":"Kobe University 5 Department of Biology, Faculty of Science , , 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2024061316413144300_JCS196469C1","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1101\/gad.196238.112","article-title":"The atypical E2F family member E2F7 couples the p53 and RB pathways during cellular senescence","volume":"26","author":"Aksoy","year":"2012","journal-title":"Genes Dev.."},{"key":"2024061316413144300_JCS196469C2","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1086\/428142","article-title":"Functional consequences of PRODH missense mutations","volume":"76","author":"Bender","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"2024061316413144300_JCS196469C3","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/j.cell.2011.03.035","article-title":"Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression","volume":"145","author":"Brady","year":"2011","journal-title":"Cell"},{"key":"2024061316413144300_JCS196469C4","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1146\/annurev-physiol-030212-183653","article-title":"Aging, cellular senescence, and cancer","volume":"75","author":"Campisi","year":"2013","journal-title":"Annu. Rev. Physiol."},{"key":"2024061316413144300_JCS196469C5","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.1101\/gad.184911.111","article-title":"E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression","volume":"26","author":"Carvajal","year":"2012","journal-title":"Genes Dev.."},{"key":"2024061316413144300_JCS196469C6","doi-asserted-by":"publisher","first-page":"4130","DOI":"10.1073\/pnas.91.10.4130","article-title":"Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells","volume":"91","author":"Chen","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024061316413144300_JCS196469C7","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1038\/nrc2440","article-title":"Living on a break: cellular senescence as a DNA-damage response","volume":"8","author":"d'Adda di Fagagna","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"2024061316413144300_JCS196469C8","doi-asserted-by":"publisher","first-page":"2540","DOI":"10.1101\/gad.8.21.2540","article-title":"DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts","volume":"8","author":"Di Leonardo","year":"1994","journal-title":"Genes Dev.."},{"key":"2024061316413144300_JCS196469C9","doi-asserted-by":"publisher","first-page":"9363","DOI":"10.1073\/pnas.92.20.9363","article-title":"A biomarker that identifies senescent human cells in culture and in aging skin in vivo","volume":"92","author":"Dimri","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024061316413144300_JCS196469C10","first-page":"1810","article-title":"Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species","volume":"61","author":"Donald","year":"2001","journal-title":"Cancer Res.."},{"key":"2024061316413144300_JCS196469C11","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1016\/0092-8674(93)90500-P","article-title":"WAF1, a potential mediator of p53 tumor suppression","volume":"75","author":"el-Deiry","year":"1993","journal-title":"Cell"},{"key":"2024061316413144300_JCS196469C12","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/7777","article-title":"The gene encoding proline dehydrogenase modulates sensorimotor gating in mice","volume":"21","author":"Gogos","year":"1999","journal-title":"Nat. Genet."},{"key":"2024061316413144300_JCS196469C13","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1007\/s11010-006-9276-6","article-title":"Overexpression of proline oxidase induces proline-dependent and mitochondria-mediated apoptosis","volume":"295","author":"Hu","year":"2007","journal-title":"Mol. Cell. Biochem."},{"key":"2024061316413144300_JCS196469C14","doi-asserted-by":"publisher","first-page":"2463","DOI":"10.1101\/gad.1971610","article-title":"The essence of senescence","volume":"24","author":"Kuilman","year":"2010","journal-title":"Genes Dev.."},{"key":"2024061316413144300_JCS196469C15","doi-asserted-by":"publisher","first-page":"6414","DOI":"10.1158\/0008-5472.CAN-09-1223","article-title":"Proline oxidase functions as a mitochondrial tumor suppressor in human cancers","volume":"69","author":"Liu","year":"2009","journal-title":"Cancer Res.."},{"key":"2024061316413144300_JCS196469C16","doi-asserted-by":"publisher","first-page":"17206","DOI":"10.1038\/srep17206","article-title":"Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides","volume":"5","author":"Liu","year":"2015","journal-title":"Sci. Rep."},{"key":"2024061316413144300_JCS196469C17","doi-asserted-by":"publisher","first-page":"1918","DOI":"10.1016\/j.yexcr.2008.01.011","article-title":"Free radicals and senescence","volume":"314","author":"Lu","year":"2008","journal-title":"Exp. Cell Res."},{"key":"2024061316413144300_JCS196469C18","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1002\/ajmg.a.31199","article-title":"Malignancy in chromosome 22q11.2 deletion syndrome (DiGeorge syndrome\/velocardiofacial syndrome)","volume":"140A","author":"McDonald-McGinn","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"2024061316413144300_JCS196469C20","doi-asserted-by":"publisher","first-page":"31758","DOI":"10.1038\/srep31758","article-title":"Identification of cellular senescence-specific genes by comparative transcriptomics","volume":"6","author":"Nagano","year":"2016","journal-title":"Sci. Rep."},{"key":"2024061316413144300_JCS196469C21","doi-asserted-by":"publisher","first-page":"e80411","DOI":"10.1371\/journal.pone.0080411","article-title":"Branched-chain amino acids enhance premature senescence through mammalian target of rapamycin complex I-mediated upregulation of p21 protein","volume":"8","author":"Nakano","year":"2013","journal-title":"PLoS ONE"},{"key":"2024061316413144300_JCS196469C22","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1006\/excr.1994.1063","article-title":"Cloning of senescent cell-derived inhibitors of DNA synthesis using an expression screen","volume":"211","author":"Noda","year":"1994","journal-title":"Exp. Cell Res."},{"key":"2024061316413144300_JCS196469C23","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/msb.2010.5","article-title":"Feedback between p21 and reactive oxygen production is necessary for cell senescence","volume":"6","author":"Passos","year":"2010","journal-title":"Mol. Syst. Biol."},{"key":"2024061316413144300_JCS196469C24","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s00726-008-0063-4","article-title":"The metabolism of proline, a stress substrate, modulates carcinogenic pathways","volume":"35","author":"Phang","year":"2008","journal-title":"Amino Acids"},{"key":"2024061316413144300_JCS196469C25","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/38525","article-title":"A model for p53-induced apoptosis","volume":"389","author":"Polyak","year":"1997","journal-title":"Nature"},{"key":"2024061316413144300_JCS196469C26","doi-asserted-by":"publisher","first-page":"e69152","DOI":"10.1371\/journal.pone.0069152","article-title":"P53 family members modulate the expression of PRODH, but not PRODH2, via intronic p53 response elements","volume":"8","author":"Raimondi","year":"2013","journal-title":"PLoS ONE"},{"key":"2024061316413144300_JCS196469C27","doi-asserted-by":"publisher","first-page":"905","DOI":"10.1083\/jcb.146.5.905","article-title":"Megabase chromatin domains involved in DNA double-strand breaks in vivo","volume":"146","author":"Rogakou","year":"1999","journal-title":"J. Cell Biol."},{"key":"2024061316413144300_JCS196469C28","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1134\/S000629791206003X","article-title":"Cyclin-dependent kinase inhibitor p21(Waf1): contemporary view on its role in senescence and oncogenesis","volume":"77","author":"Romanov","year":"2012","journal-title":"Biochemistry (Mosc.)"},{"key":"2024061316413144300_JCS196469C29","doi-asserted-by":"publisher","first-page":"5129","DOI":"10.1038\/onc.2012.640","article-title":"Senescence and aging: the critical roles of p53","volume":"32","author":"Rufini","year":"2013","journal-title":"Oncogene"},{"key":"2024061316413144300_JCS196469C30","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1101\/gad.235184.113","article-title":"Cellular senescence and its effector programs","volume":"28","author":"Salama","year":"2014","journal-title":"Genes Dev.."},{"key":"2024061316413144300_JCS196469C31","doi-asserted-by":"crossref","first-page":"3088","DOI":"10.1128\/iai.64.8.3088-3092.1996","article-title":"Intact immune defenses are required for mice to resist the ts-4 vaccine strain of Toxoplasma gondii","volume":"64","author":"Sayles","year":"1996","journal-title":"Infect. Immun."},{"key":"2024061316413144300_JCS196469C32","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1126\/science.1106653","article-title":"Extension of murine life span by overexpression of catalase targeted to mitochondria","volume":"308","author":"Schriner","year":"2005","journal-title":"Science"},{"key":"2024061316413144300_JCS196469C33","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1083\/jcb.151.7.1381","article-title":"p53 binding protein 1 (53BP1) is an early participant in the cellular response to DNA double-strand breaks","volume":"151","author":"Schultz","year":"2000","journal-title":"J. Cell Biol."},{"key":"2024061316413144300_JCS196469C34","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/S0092-8674(00)81902-9","article-title":"Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a","volume":"88","author":"Serrano","year":"1997","journal-title":"Cell"},{"key":"2024061316413144300_JCS196469C35","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1017\/S1461145709000492","article-title":"Analysis of prepulse inhibition in mouse lines overexpressing 22q11.2 orthologues","volume":"12","author":"Stark","year":"2009","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"2024061316413144300_JCS196469C36","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1016\/j.pep.2012.01.021","article-title":"Expression in Escherichia coli of the catalytic domain of human proline oxidase","volume":"82","author":"Tallarita","year":"2012","journal-title":"Protein Expr. Purif."},{"key":"2024061316413144300_JCS196469C37","first-page":"1876","article-title":"DNA damage is able to induce senescence in tumor cells in vitro and in vivo","volume":"62","author":"te Poele","year":"2002","journal-title":"Cancer Res.."},{"key":"2024061316413144300_JCS196469C38","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/j.celrep.2013.04.012","article-title":"p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa","volume":"3","author":"Valente","year":"2013","journal-title":"Cell Rep."},{"key":"2024061316413144300_JCS196469C39","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.cell.2009.04.037","article-title":"Blinded by the light: the growing complexity of p53","volume":"137","author":"Vousden","year":"2009","journal-title":"Cell"},{"key":"2024061316413144300_JCS196469C40","first-page":"1078","article-title":"Topoisomerase II-reactive chemotherapeutic drugs induce apoptosis in thymocytes","volume":"51","author":"Walker","year":"1991","journal-title":"Cancer Res.."},{"key":"2024061316413144300_JCS196469C41","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.cmet.2012.02.013","article-title":"Impaired insulin\/IGF1 signaling extends life span by promoting mitochondrial L-proline catabolism to induce a transient ROS signal","volume":"15","author":"Zarse","year":"2012","journal-title":"Cell Metab.."},{"key":"2024061316413144300_JCS196469C42","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.3748\/wjg.v10.i13.1975","article-title":"Loss of heterozygosity on chromosome 10q22-10q23 and 22q11.2-22q12.1 and p53 gene in primary hepatocellular carcinoma","volume":"10","author":"Zhu","year":"2004","journal-title":"World J. Gastroenterol."}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/jcs.196469","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/130\/8\/1413\/3498242\/jcs196469.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.196469\/2057546\/jcs196469.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/130\/8\/1413\/3498242\/jcs196469.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T16:59:43Z","timestamp":1718297983000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/130\/8\/1413\/56708\/Proline-dehydrogenase-promotes-senescence-through"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,15]]},"references-count":41,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2017,4,15]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.196469","relation":{},"ISSN":["1477-9137","0021-9533"],"issn-type":[{"value":"1477-9137","type":"electronic"},{"value":"0021-9533","type":"print"}],"subject":[],"published":{"date-parts":[[2017,4,15]]}}}