title: Prolyl isomerase Pin1-mediated conformational change and subnuclear focal accumulation of Runx2 are crucial for fibroblast growth factor 2 (FGF2)-induced osteoblast differentiation.
abstract: Fibroblast growth factor 2 (FGF2) signaling plays a pivotal role in bone growth/differentiation through the activation of osteogenic master transcription factor Runx2, which is mediated by the ERK/MAPK-dependent phosphorylation and the p300-dependent acetylation of Runx2. In this study, we found that Pin1-dependent isomerization of Runx2 is the critical step for FGF2-induced Runx2 transactivation function. We identified four serine or threonine residues in the C-terminal domain of Runx2 that are responsible for Pin1 binding and structural modification. Confocal imaging studies indicated that FGF2 treatment strongly stimulated the focal accumulation of Pin1 in the subnuclear area, which recruited Runx2. In addition, active forms of RNA polymerase-II also colocalized in the same subnuclear compartment. Dipentamethylene thiuram monosulfide, a Pin1 inhibitor, strongly attenuated their focal accumulation as well as Runx2 transactivation activity. The Pin1-mediated structural modification of Runx2 is an indispensable step connecting phosphorylation and acetylation and, consequently, transcriptional activation of Runx2 by FGF signaling. Thus, the modulation of Pin1 activity may be a target for the regulation of bone formation.
authors: From the Department of Molecular Genetics, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 110-749 and.
authors: Won-Joon
authors: WJ
authors: Yoon
authors: Young-Dan
authors: YD
authors: Cho
authors: Woo-Jin
authors: WJ
authors: Kim
authors: Han-Sol
authors: HS
authors: Bae
authors: Rabia
authors: R
authors: Islam
authors: Kyung-Mi
authors: KM
authors: Woo
authors: Jeong-Hwa
authors: JH
authors: Baek
authors: Suk-Chul
authors: SC
authors: Bae
authors: Hyun-Mo
authors: HM
authors: Ryoo
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D050659:Core Binding Factor Alpha 1 Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects; D019696:Peptidylprolyl Isomerase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D016222:Fibroblast Growth Factor 2; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse
keywords: Acetylation; Cell Differentiation; FGF Signaling; Osteoblasts; Pin1; Protein Conformation; Protein Phosphorylation; Runx2; Subnuclear Accumulation; Transcription Factors