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TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects

Ying Feng1, Nana Lee, Eric R Fearon

  • 1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.

Cancer Research
|December 26, 2003
PubMed

Insights

TIP49 protein acts as a cofactor in beta-catenin/T-cell factor (TCF) gene regulation. Inhibiting TIP49 function blocks cancer cell growth and TCF-dependent gene expression, suggesting a role in chromatin remodeling.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Epigenetics

Background:

  • Beta-catenin is crucial for Wnt signaling and T-cell factor (TCF)-mediated transcription.
  • Dysregulated beta-catenin is implicated in numerous cancers, driving neoplastic transformation.
  • Factors cooperating with beta-catenin in gene transcription remain incompletely understood.

Purpose of the Study:

  • To investigate the role of TIP49 as a cofactor in beta-catenin/TCF-mediated transcription.
  • To determine the impact of TIP49 on neoplastic transformation and TCF-dependent gene expression.
  • To elucidate the mechanism by which TIP49 influences gene regulation, potentially involving chromatin remodeling.

Main Methods:

  • Utilized an ATPase-deficient TIP49 mutant (TIP49D302N) to inhibit beta-catenin function.
  • Employed small interfering RNA (siRNA) to reduce endogenous TIP49 levels.
  • Performed chromatin immunoprecipitation (ChIP) assays to assess protein-DNA interactions and histone acetylation.
  • Analyzed the expression of TCF-dependent genes, including ITF-2.

Main Results:

  • TIP49 inhibition, via TIP49D302N or siRNA, significantly reduced beta-catenin-mediated neoplastic transformation and anchorage-independent growth of cancer cells.
  • TIP49 inhibition suppressed the activation of beta-catenin/TCF-dependent genes.
  • TIP49 was found in complexes with chromatin remodeling factors and co-immunoprecipitated with TIP60 and TRRAP.
  • TIP49, TIP60, and TRRAP interact with regulatory regions of TCF-dependent genes like ITF-2.
  • TIP49 inhibition led to decreased histone acetylation at TCF-binding sites in the ITF-2 promoter.

Conclusions:

  • TIP49 functions as a critical cofactor in beta-catenin/TCF gene regulation in both normal and cancer cells.
  • TIP49 likely exerts its function through involvement in chromatin remodeling processes.
  • Targeting TIP49 may represent a therapeutic strategy for cancers with aberrant Wnt/beta-catenin signaling.

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