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Updated: May 5, 2026

Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
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Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis

Published on: June 27, 2020

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The multifunctional protein fused in sarcoma (FUS) is a coactivator of microphthalmia-associated transcription factor

Agnieszka Bronisz1, Heather A Carey, Jakub Godlewski

  • 1From the Department of Molecular and Cellular Biochemistry, Comprehensive Cancer Center, and.

The Journal of Biological Chemistry
|November 22, 2013
PubMed

Insights

The proto-oncogene FUS partners with MITF and BRG1 to regulate osteoclast differentiation. This complex formation, controlled by p38 MAPK phosphorylation, is crucial for gene expression during osteoclastogenesis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The microphthalmia-associated transcription factor (MITF) is essential for osteoclast differentiation, mediating signals from CSF-1 and RANKL.
  • MITF's regulatory functions depend on its interactions with various cofactors, which are not fully understood.
  • Identifying MITF partners is key to understanding gene regulation in osteoclastogenesis.

Purpose of the Study:

  • To identify novel cofactors of MITF involved in osteoclast differentiation.
  • To elucidate the molecular mechanisms by which MITF regulates gene expression in osteoclasts.
  • To investigate the role of p38 MAPK signaling in MITF-mediated transcriptional control.

Main Methods:

  • Co-immunoprecipitation assays to identify protein complexes.
  • Chromatin immunoprecipitation (ChIP) to assess promoter recruitment.
  • siRNA-mediated knockdown to evaluate gene function.
  • Western blotting to detect protein modifications like phosphorylation and sumoylation.

Main Results:

  • A trimeric complex of FUS, BRG1, and MITF was identified, regulated by p38 MAPK-dependent phosphorylation of MITF at Ser-307.
  • FUS was recruited to the promoters of osteoclast-specific genes (Acp5, Ctsk) during differentiation.
  • FUS knockdown impaired the transcription of Acp5 and Ctsk.
  • MITF sumoylation at Lys-316 inhibited its interaction with FUS and BRG1 in a manner dependent on p38 MAPK phosphorylation.

Conclusions:

  • FUS acts as a critical co-regulator of MITF activity in osteoclasts.
  • The RANKL/p38 MAPK signaling pathway controls osteoclast gene expression through the regulation of the MITF-FUS-BRG1 complex.
  • This study provides new insights into the molecular mechanisms governing osteoclast differentiation.
Keywords:
Cell DifferentiationOsteoclastPhosphorylationSumoylationTranscription Coactivators

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