TY - JOUR
T1 - Reciprocal regulation of acetyl-CoA carboxylase 1 and senescence in human fibroblasts involves oxidant mediated p38 MAPK activation
AU - Marmisolle, Inés
AU - Martínez, Jennyfer
AU - Liu, Jie
AU - Mastrogiovanni, Mauricio
AU - Fergusson, María M.
AU - Rovira, Ilsa I.
AU - Castro, Laura
AU - Trostchansky, Andrés
AU - Moreno, María
AU - Cao, Liu
AU - Finkel, Toren
AU - Quijano, Celia
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
KW - Acetyl-CoA carboxylase 1
KW - Cellular senescence
KW - DNA damage response
KW - Lipid synthesis
KW - p38 MAPK
KW - Reactive oxygen species (ROS)
UR - http://www.scopus.com/inward/record.url?scp=84994381544&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994381544&partnerID=8YFLogxK
U2 - 10.1016/j.abb.2016.10.016
DO - 10.1016/j.abb.2016.10.016
M3 - Article
C2 - 27983949
AN - SCOPUS:84994381544
SN - 0003-9861
VL - 613
SP - 12
EP - 22
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
ER -