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Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation.
- Source :
-
Archives of biochemistry and biophysics [Arch Biochem Biophys] 2017 Jan 01; Vol. 613, pp. 12-22. Date of Electronic Publication: 2016 Oct 27. - Publication Year :
- 2017
-
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.<br /> (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Subjects :
- Cell Proliferation
Cellular Senescence
Fatty Acids chemistry
Fibroblasts enzymology
Gene Deletion
Gene Expression Profiling
Gene Expression Regulation
Humans
Lentivirus
Lipids chemistry
MAP Kinase Signaling System
Oxidants chemistry
RNA, Messenger metabolism
Reactive Oxygen Species metabolism
Acetyl-CoA Carboxylase metabolism
Gene Expression Regulation, Enzymologic
p38 Mitogen-Activated Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-0384
- Volume :
- 613
- Database :
- MEDLINE
- Journal :
- Archives of biochemistry and biophysics
- Publication Type :
- Academic Journal
- Accession number :
- 27983949
- Full Text :
- https://doi.org/10.1016/j.abb.2016.10.016