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)