Mutant p62P392L Stimulation of Osteoclast Differentiation in Paget's Disease of Bone
| Autor: | D. Sudhaker Rao, Sakamuri V. Reddy, Srinivasan Shanmugarajan, Kumaran Sundaram |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Sequestosome-1 Protein
medicine.medical_specialty Osteoclasts Biology Bone resorption Small hairpin RNA Mice Endocrinology Sequestosome 1 Osteoclast Internal medicine medicine Animals Bone Resorption education General Endocrinology Transcription factor Heat-Shock Proteins Adaptor Proteins Signal Transducing education.field_of_study Receptor Activator of Nuclear Factor-kappa B RANK Ligand Autosomal dominant trait Cell Differentiation Osteitis Deformans medicine.anatomical_structure Mutation Signal transduction Signal Transduction |
| Zdroj: | Endocrinology. 152:4180-4189 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2011-1225 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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