Oncogenic activation of c-Myb correlates with a loss of negative regulation by TIF1beta and Ski

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Published on: June 6, 2025

Teruaki Nomura1, Jun Tanikawa, Hiroshi Akimaru

  • 1Laboratory of Molecular Genetics, RIKEN Tsukuba Institute, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.

The Journal of Biological Chemistry
|February 6, 2004
PubMed

Insights

TIF1beta and corepressors like Ski bind c-Myb, inhibiting hematopoietic cell proliferation. Mutations weakening these interactions activate the oncogene, revealing a key mechanism in nuclear oncogene activation.

Area of Science:

  • Molecular Biology
  • Oncology
  • Gene Regulation

Background:

  • The c-myb proto-oncogene product (c-Myb) is crucial for hematopoietic cell proliferation.
  • Dysregulation of c-Myb, particularly through mutations in its negative regulatory domain (NRD), leads to oncogenic activation.

Purpose of the Study:

  • To investigate the role of TIF1beta and associated corepressors in regulating c-Myb activity.
  • To elucidate the molecular mechanisms underlying c-Myb oncogenic activation.

Main Methods:

  • Co-immunoprecipitation assays to study protein-protein interactions between c-Myb, TIF1beta, and corepressors (Ski, N-CoR, mSin3A).
  • Reporter gene assays to assess c-Myb-dependent trans-activation.
  • Studies in Drosophila to examine the function of the TIF1beta homolog, Bonus.

Main Results:

  • TIF1beta directly binds to the c-Myb NRD and negatively regulates its trans-activation.
  • Corepressors Ski, N-CoR, and mSin3A bind to the c-Myb DNA-binding domain, forming a complex with TIF1beta and recruiting histone deacetylases.
  • The Drosophila TIF1beta homolog, Bonus, negatively regulates Drosophila Myb activity.
  • Ski competes with the coactivator CBP for c-Myb binding, highlighting the importance of corepressor-coactivator selection.
  • Mutations in c-Myb's NRD or DNA-binding domain reduce corepressor interaction, weakening negative regulation.

Conclusions:

  • TIF1beta and corepressors act as negative regulators of c-Myb activity by binding to distinct domains and modulating its transcriptional function.
  • The interaction between c-Myb and its corepressors is critical for preventing oncogenic activation.
  • Understanding these regulatory interactions provides insights into the activation mechanisms of nuclear oncogenes.

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