Linkage of M-CSF signaling to Mitf, TFE3, and the osteoclast defect in Mitf(mi/mi) mice

Autor: Clifford M. Takemoto, Timothy J. Hemesath, Gabriela Motyckova, Audrey G. Wells, David E. Fisher, Wade E. Huber, Katherine N. Weilbaecher, Nikki Dowland, Christine L. Hershey, Ying Xu
Rok vydání: 2001
Předmět:
musculoskeletal diseases
MAPK/ERK pathway
medicine.medical_specialty
MAP Kinase Signaling System
Amino Acid Motifs
Green Fluorescent Proteins
Osteoclasts
Mice
Inbred Strains
Biology
Bone resorption
Mice
Osteoclast
Internal medicine
Coactivator
medicine
Animals
Humans
Phosphorylation
Molecular Biology
Transcription factor
Cells
Cultured
Microphthalmia-Associated Transcription Factor
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Macrophage Colony-Stimulating Factor
Macrophages
Cell Differentiation
Cell Biology
Microphthalmia-associated transcription factor
Immunohistochemistry
Cell biology
DNA-Binding Proteins
Luminescent Proteins
Endocrinology
medicine.anatomical_structure
Osteopetrosis
Indicators and Reagents
Signal transduction
Mitogen-Activated Protein Kinases
Transcription Factors
Zdroj: Molecular cell. 8(4)
ISSN: 1097-2765
Popis: Osteoclasts are multinucleated hematopoietic cells essential for bone resorption. Macrophage colony-stimulating factor (M-CSF) is critical for osteoclast development and function, although its nuclear targets in osteoclasts are largely unknown. Mitf and TFE3 are two closely related helix-loop-helix (HLH) transcription factors previously implicated in osteoclast development and function. We demonstrate that cultured Mitf(mi/mi) osteoclasts are immature, mononuclear, express low levels of TRAP, and fail to mature upon M-CSF stimulation. In addition, M-CSF induces phosphorylation of Mitf and TFE3 via a conserved MAPK consensus site, thereby triggering their recruitment of the coactivator p300. Furthermore, an unphosphorylatable mutant at the MAPK consensus serine is specifically deficient in formation of multinucleated osteoclasts, mimicking the defect in Mitf(mi/mi) mice. These results identify a signaling pathway that appears to coordinate cytokine signaling with the expression of genes vital to osteoclast development.
Databáze: OpenAIRE
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