Abstract
The microphthalmia-associated transcription factor (MITF) is required for terminal osteoclast differentiation and is a signaling effector engaged by macrophage colony-stimulating factor 1 (CSF-1) and receptor activator of nuclear factor-κB ligand (RANKL). MITF exerts its regulatory functions through its association with cofactors. Discovering the identity of its various partners will provide insights into the mechanisms governing gene expression during osteoclastogenesis. Here, we demonstrate that the proto-oncogene fused in sarcoma (FUS), the chromatin remodeling ATPase BRG1, and MITF form a trimeric complex that is regulated by phosphorylation of MITF at Ser-307 by p38 MAPK during osteoclast differentiation. FUS was recruited to MITF target gene promoters Acp5 and Ctsk during osteoclast differentiation, and FUS knockdown abolished efficient transcription of Acp5 and Ctsk. Furthermore, sumoylation of MITF at Lys-316, known to negatively regulate MITF transcriptional activity, inhibited MITF interactions with FUS and BRG1 in a p38 MAPK phosphorylation-dependent manner. These results demonstrate that FUS is a coregulator of MITF activity and provide new insights into how the RANKL/p38 MAPK signaling nexus controls gene expression in osteoclasts.
Keywords:
Cell Differentiation; Osteoclast; Phosphorylation; Sumoylation; Transcription Coactivators.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acid Phosphatase / biosynthesis
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Acid Phosphatase / genetics
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Animals
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COS Cells
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Cathepsin K / biosynthesis
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Cathepsin K / genetics
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Chlorocebus aethiops
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DNA Helicases / genetics
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DNA Helicases / metabolism*
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Gene Expression Regulation / physiology
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Humans
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Isoenzymes / biosynthesis
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Isoenzymes / genetics
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MAP Kinase Signaling System / physiology
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Mice
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Microphthalmia-Associated Transcription Factor / genetics
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Microphthalmia-Associated Transcription Factor / metabolism*
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Osteoclasts / cytology
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Osteoclasts / metabolism*
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Phosphorylation / physiology
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Promoter Regions, Genetic / physiology*
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Proto-Oncogene Mas
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RANK Ligand / genetics
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RANK Ligand / metabolism
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RNA-Binding Protein FUS
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Tartrate-Resistant Acid Phosphatase
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic / physiology*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Isoenzymes
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MAS1 protein, human
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Microphthalmia-Associated Transcription Factor
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Mitf protein, mouse
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Multiprotein Complexes
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Nuclear Proteins
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Proto-Oncogene Mas
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RANK Ligand
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RNA-Binding Protein FUS
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Tnfsf11 protein, mouse
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Transcription Factors
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p38 Mitogen-Activated Protein Kinases
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ACP5 protein, human
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Acid Phosphatase
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Acp5 protein, mouse
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Tartrate-Resistant Acid Phosphatase
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Cathepsin K
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Ctsk protein, mouse
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Smarca4 protein, mouse
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DNA Helicases