title: Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation.
abstract: We sought to explore the fate of the fatty acid synthesis pathway in human fibroblasts exposed to DNA damaging agents capable of inducing senescence, a state of irreversible growth arrest. Induction of premature senescence by doxorubicin or hydrogen peroxide led to a decrease in protein and mRNA levels of acetyl-CoA carboxylase 1 (ACC1), the enzyme that catalyzes the rate-limiting step in fatty-acid biosynthesis. ACC1 decay accompanied the activation of the DNA damage response (DDR), and resulted in decreased lipid synthesis. A reduction in protein and mRNA levels of ACC1 and in lipid synthesis was also observed in human primary fibroblasts that underwent replicative senescence. We also explored the consequences of inhibiting fatty acid synthesis in proliferating non-transformed cells. Using shRNA technology, we knocked down ACC1 in human fibroblasts. Interestingly, this metabolic perturbation was sufficient to arrest proliferation and trigger the appearance of several markers of the DDR and increase senescence associated β-galactosidase activity. Reactive oxygen species and p38 mitogen activated protein kinase phosphorylation participated in the induction of senescence. Similar results were obtained upon silencing of fatty acid synthase (FAS) expression. Together our results point towards a tight coordination of fatty acid synthesis and cell proliferation in human fibroblasts.
authors.affiliation: Center for Free Radical and Biomedical Research and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Inés
authors.initials: I
authors.lastname: Marmisolle
authors.affiliation: Center for Free Radical and Biomedical Research and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Jennyfer
authors.initials: J
authors.lastname: Martínez
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Center for Free Radical and Biomedical Research and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Mastrogiovanni
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: María M
authors.initials: MM
authors.lastname: Fergusson
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Ilsa I
authors.initials: II
authors.lastname: Rovira
authors.affiliation: Center for Free Radical and Biomedical Research and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Laura
authors.initials: L
authors.lastname: Castro
authors.affiliation: Center for Free Radical and Biomedical Research and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Andrés
authors.initials: A
authors.lastname: Trostchansky
authors.affiliation: Laboratory for Vaccine Research, Departamento de Desarrollo Biotecnológico, Facultad de Medicina, Instituto de Higiene, Universidad de la República, Uruguay.
authors.forename: María
authors.initials: M
authors.lastname: Moreno
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Liu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Center for Molecular Medicine, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address: finkelt@nhlbi.nih.gov.
authors.forename: Toren
authors.initials: T
authors.lastname: Finkel
authors.affiliation: Center for Free Radical and Biomedical Research and Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay. Electronic address: celiq@fmed.edu.uy.
authors.forename: Celia
authors.initials: C
authors.lastname: Quijano
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D049109:Cell Proliferation; D016922:Cellular Senescence; D005227:Fatty Acids / Q000737:chemistry; D005347:Fibroblasts / Q000201:enzymology; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D016086:Lentivirus; D008055:Lipids / Q000737:chemistry; D020935:MAP Kinase Signaling System; D016877:Oxidants / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D008055:Lipids; D016877:Oxidants; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase
keywords: Acetyl-CoA carboxylase 1; Cellular senescence; DNA damage response; Lipid synthesis; Reactive oxygen species (ROS); p38 MAPK