title: Mutant p62P392L stimulation of osteoclast differentiation in Paget's disease of bone.
abstract: Paget's disease of the bone (PDB) is an autosomal dominant trait with genetic heterogeneity, characterized by abnormal osteoclastogenesis. Sequestosome 1 (p62) is a scaffold protein that plays an important role in receptor activator of nuclear factor κB (RANK) signaling essential for osteoclast (OCL) differentiation. p62P392L mutation in the ubiquitin-associated (UBA) domain is widely associated with PDB; however, the mechanisms by which p62P392L stimulate OCL differentiation in PDB are not completely understood. Deubiquitinating enzyme cylindromatosis (CYLD) has been shown to negatively regulate RANK ligand-RANK signaling essential for OCL differentiation. Here, we report that CYLD binds with the p62 wild-type (p62WT), non-UBA mutant (p62A381V) but not with the UBA mutant (p62P392L) in OCL progenitor cells. Also, p62P392L induces expression of c-Fos (2.8-fold) and nuclear factor of activated T cells c1 (6.0-fold) transcription factors critical for OCL differentiation. Furthermore, p62P392L expression results in accumulation of polyubiquitinated TNF receptor-associated factor (TRAF)6 and elevated levels of phospho-IκB during OCL differentiation. Retroviral transduction of p62P392L/CYLD short hairpin RNA significantly increased TRAP positive multinucleated OCL formation/bone resorption activity in mouse bone marrow cultures. Thus, the p62P392L mutation abolished CYLD interaction and enhanced OCL development/bone resorption activity in PDB.
authors: Charles P. Darby Children's Research Institute, Medical University of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29425, USA.
authors: Kumaran
authors: K
authors: Sundaram
authors: Srinivasan
authors: S
authors: Shanmugarajan
authors: D Sudhaker
authors: DS
authors: Rao
authors: Sakamuri V
authors: SV
authors: Reddy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010001:Osteitis Deformans / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000502:physiology*; D053245:RANK Ligand / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse