title: Negative feedback control of osteoclast formation through ubiquitin-mediated down-regulation of NFATc1.
abstract: The regulation of NFATc1 expression is important for osteoclast differentiation and function. Herein, we demonstrate that macrophage-colony-stimulating factor induces NFATc1 degradation via Cbl proteins in a Src kinase-dependent manner. NFATc1 proteins are ubiquitinated and rapidly degraded during late stage osteoclastogenesis, and this degradation is mediated by Cbl-b and c-Cbl ubiquitin ligases in a Src-dependent manner. In addition, NFATc1 interacts endogenously with c-Src, c-Cbl, and Cbl-b in osteoclasts. Overexpression of c-Src induces down-regulation of NFATc1, and depletion of Cbl proteins blocks NFATc1 degradation during late stage osteoclastogenesis. Taken together, our data provide a negative regulatory mechanism by which macrophage-colony-stimulating factor activates Src family kinases and Cbl proteins, and subsequently, induces NFATc1 degradation during osteoclast differentiation.
authors.affiliation: National Research Laboratory for Regulation of Bone Metabolism and Disease, Medical Research Center for Gene Regulation, Research Institute of Medical Sciences, Brain Korea 21, Chonnam National University Medical School, Gwangju 501-746, Korea.
authors.forename: Jung Ha
authors.initials: JH
authors.lastname: Kim
authors.forename: Kabsun
authors.initials: K
authors.lastname: Kim
authors.forename: Hye Mi
authors.initials: HM
authors.lastname: Jin
authors.forename: Insun
authors.initials: I
authors.lastname: Song
authors.forename: Bang Ung
authors.initials: BU
authors.lastname: Youn
authors.forename: Seoung-Hoon
authors.initials: SH
authors.lastname: Lee
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.forename: Nacksung
authors.initials: N
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D025801:Ubiquitin; D016173:Macrophage Colony-Stimulating Factor; D050721:Proto-Oncogene Proteins c-cbl; D016392:Proto-Oncogene Proteins pp60(c-src); C493849:Cbl protein, mouse