Notch1 signaling in FIZZ1 induction of myofibroblast differentiation.
Notch1 is an evolutionarily conserved receptor that regulates cell fate, including such events as differentiation, proliferation, and apoptosis. Myofibroblast differentiation is a key feature of lung fibrosis. Found in inflammatory zone 1 (FIZZ1) has direct fibrogenic properties because of its ability to induce myofibroblast differentiation. However, the downstream signaling pathway that mediates FIZZ1 induction of myofibroblast differentiation remains unknown. The objective of this study was to investigate the involvement of Notch signaling in FIZZ1 induction of lung myofibroblast differentiation and thus explore the potential role of Notch1 in pulmonary fibrosis. The results showed that FIZZ1 increased the expression levels of activated intracellular domain of Notch1 (NIC), its ligand Jagged1, and its target gene Hes1, which were associated with elevated alpha-smooth muscle actin expression levels. Fibroblast alpha-smooth muscle actin expression is induced by the overexpression of NIC but is suppressed by the inhibition of NIC. Moreover, lung fibroblasts that were isolated from mice lacking the GDP-4-keto-6-deoxymannose3,5-epimerase-4-reductase enzyme (FX knockout) exhibited significantly reduced responsiveness to FIZZ1, which was reversed by fucose supplementation. In the absence of exogenous fucose, these FX-deficient cells exhibited defective fucosylation, which is required for Notch signaling. These knockout mice also showed impaired lung fibrosis. These findings suggest that Notch1 signaling in response to FIZZ1 may play a significant role in myofibroblast differentiation during lung fibrosis.
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109-2200, USA.
Tianju
T
Liu
Biao
B
Hu
Yoon Young
YY
Choi
Myoungja
M
Chung
Matthew
M
Ullenbruch
Hongfeng
H
Yu
John B
JB
Lowe
Sem H
SH
Phan
D000199:Actins / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005643:Fucose / Q000008:administration & dosage; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006836:Hydro-Lyases / Q000502:physiology; D006909:Hydroxyproline / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008168:Lung / Q000166:cytology* / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1
D000199:Actins; D000903:Antibiotics, Antineoplastic; D051792:Basic Helix-Loop-Helix Proteins; D001761:Bleomycin; D002135:Calcium-Binding Proteins; D005643:Fucose; D018398:Homeodomain Proteins; D006836:Hydro-Lyases; D006909:Hydroxyproline; D036341:Intercellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D000072099:Serrate-Jagged Proteins; D000072056:Transcription Factor HES-1; C489734:Hes1 protein, mouse; C000606274:Jag1 protein, mouse; C497762:Notch1 protein, mouse; C413576:Retnla protein, mouse; C044971:GDPmannose 4,6-dehydratase