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MOZ-TIF2 inhibits transcription by nuclear receptors and p53 by impairment of CBP function

Karin B Kindle1, Philip J F Troke, Hilary M Collins

  • 1School of Pharmacy, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.

Molecular and Cellular Biology
|January 20, 2005
PubMed

Insights

The MOZ-TIF2 fusion protein in acute myeloid leukemia (AML) inhibits normal CBP protein function. This disruption impairs CBP-dependent gene activation and cellular processes, contributing to AML development.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • Cellular Biology

Background:

  • Chromosomal rearrangements involving MOZ/MORF and TIF2/p300/CBP are implicated in acute myeloid leukemia (AML).
  • These rearrangements create fusion proteins that may disrupt normal cellular functions.

Purpose of the Study:

  • To investigate the mechanism by which the MOZ-TIF2 fusion protein contributes to AML pathogenesis.
  • To determine the functional interaction of MOZ-TIF2 with CBP (CREB-binding protein) and its downstream effects.

Main Methods:

  • Coimmunoprecipitation and fluorescent resonance energy transfer (FRET) assays to study protein interactions.
  • In vitro assays using murine bone marrow cells to assess cellular proliferation.
  • Analysis of protein localization and cellular CBP levels.

Main Results:

  • MOZ-TIF2 acts as a dominant inhibitor of CBP-dependent transcriptional activators, including nuclear receptors and p53.
  • The CBP-binding domain (AD1) of MOZ-TIF2 is essential for its dominant-negative activity and its ability to enhance cell proliferation.
  • MOZ-TIF2 causes aberrant nuclear distribution and reduces cellular CBP levels, leading to CBP depletion from PML bodies.

Conclusions:

  • MOZ-TIF2 disrupts the normal function of CBP and CBP-dependent activators.
  • This disruption is a key mechanism in the action of MOZ-TIF2 in acute myeloid leukemia.
  • Targeting CBP function or MOZ-TIF2 interactions could be potential therapeutic strategies for AML.

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