RRC ID |
38899
|
著者 |
Mishima K, Kitoh H, Ohkawara B, Okuno T, Ito M, Masuda A, Ishiguro N, Ohno K.
|
タイトル |
Lansoprazole Upregulates Polyubiquitination of the TNF Receptor-Associated Factor 6 and Facilitates Runx2-mediated Osteoblastogenesis.
|
ジャーナル |
EBioMedicine
|
Abstract |
The transcription factor, runt-related transcription factor 2 (Runx2), plays a pivotal role in the differentiation of the mesenchymal stem cells to the osteochondroblast lineages. We found by the drug repositioning strategy that a proton pump inhibitor, lansoprazole, enhances nuclear accumulation of Runx2 and induces osteoblastogenesis of human mesenchymal stromal cells. Systemic administration of lansoprazole to a rat femoral fracture model increased osteoblastogenesis. Dissection of signaling pathways revealed that lansoprazole activates a noncanonical bone morphogenic protein (BMP)-transforming growth factor-beta (TGF-β) activated kinase-1 (TAK1)-p38 mitogen-activated protein kinase (MAPK) pathway. We found by in cellulo ubiquitination studies that lansoprazole enhances polyubiquitination of the TNF receptor-associated factor 6 (TRAF6) and by in vitro ubiquitination studies that the enhanced polyubiquitination of TRAF6 is attributed to the blocking of a deubiquitination enzyme, cylindromatosis (CYLD). Structural modeling and site-directed mutagenesis of CYLD demonstrated that lansoprazole tightly fits in a pocket of CYLD where the C-terminal tail of ubiquitin lies. Lansoprazole is a potential therapeutic agent for enhancing osteoblastic differentiation.
|
巻・号 |
2(12)
|
ページ |
2046-61
|
公開日 |
2015-12-1
|
DOI |
10.1016/j.ebiom.2015.11.024
|
PII |
S2352-3964(15)30209-7
|
PMID |
26844285
|
PMC |
PMC4703748
|
MeSH |
Animals
Bone Morphogenetic Proteins / metabolism
Cell Differentiation
Cell Line
Core Binding Factor Alpha 1 Subunit / genetics*
Core Binding Factor Alpha 1 Subunit / metabolism
Fracture Healing
Fractures, Bone
Humans
Lansoprazole / chemistry
Lansoprazole / pharmacology*
MAP Kinase Kinase Kinases / metabolism
Male
Mice
Models, Molecular
Molecular Conformation
Osteoblasts / cytology
Osteoblasts / drug effects*
Osteoblasts / metabolism*
Osteogenesis / drug effects*
Osteogenesis / genetics*
Protein Transport
Proton Pump Inhibitors / pharmacology
Rats
Signal Transduction / drug effects
TNF Receptor-Associated Factor 6 / metabolism*
Ubiquitination / drug effects
Ubiquitins / chemistry
Ubiquitins / metabolism
p38 Mitogen-Activated Protein Kinases / metabolism
|
IF |
5.736
|
引用数 |
7
|
リソース情報 |
ヒト・動物細胞 |
UCB408E6E7TERT-33(RCB2080) |