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TIP49 Regulates ß-Catenin-Mediated Neoplastic Transformation and T-Cell Factor Target Gene Induction via Effects on Chromatin Remodeling

¹ Departments of Internal Medicine,
² Pathology, and
³ Human Genetics, and
⁴ The Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan and
⁵ DNA Software Inc., Ann Arbor, Michigan

ß-Catenin has a key role in Wnt signaling via effects on T-cell factor (TCF)-mediated transcription. Mutational defects in ß-catenin regulation are seen in many cancers, leading to elevated ß-catenin levels, enhanced binding of ß-catenin to TCFs, and increased expression of TCF-regulated genes. Factors cooperating with ß-catenin in transcription of TCF-regulated genes are not well defined. TIP49, an ATPase previously implicated as a cofactor for oncogenic transformation by c-Myc, has been shown to bind to ß-catenin. We found that expression of an ATPase-deficient mutant form of TIP49 (TIP49D302N) substantially inhibited ß-catenin-mediated neoplastic transformation of immortalized rat epithelial cells and anchorage-independent growth of human colon cancer cells with deregulated ß-catenin. The TIP49D302N mutant inhibited ß-catenin-mediated activation of TCF-dependent cellular genes. Similar inhibition of the expression of ß-catenin/TCF-dependent genes was seen with small interfering RNA approaches against endogenous TIP49. TIP49 was found in complexes with chromatin remodeling and histone-modifying factors and cofactors, including the TIP60 histone acetylase-associated proteins transactivation/transformation-domain associated protein (TRRAP) and BAF53. Using chromatin immunoprecipitation methods, the TIP49, TIP60, and TRRAP proteins were found to interact with sequences in the regulatory region of the gene for ITF-2, a TCF-dependent cellular gene. The ability of TIP49D302N to inhibit ITF-2 gene expression was linked to decreased acetylation of histones in the vicinity of the TCF-binding sites in the ITF-2 promoter region. We suggest that TIP49 is an important cofactor in ß-catenin/TCF gene regulation in normal and neoplastic cells, likely functioning in chromatin remodeling.

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