TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling.
TIP49 regulates beta-catenin-mediated neoplastic transformation and T-cell factor target gene induction via effects on chromatin remodeling.
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发表时间：
2003-12
期刊：
影响因子：
11.2
通讯作者：
Ying Feng;Nana (Hyung-Ran) Lee;E. Fearon
中科院分区：
文献类型：
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作者：
Ying Feng;Nana (Hyung-Ran) Lee;E. Fearon
β-连环蛋白通过影响 T 细胞因子 (TCF) 介导的转录，在 Wnt 信号传导中发挥关键作用。许多癌症中都存在 β-连环蛋白调控的突变缺陷，导致 β-连环蛋白水平升高、β-连环蛋白与 TCF 的结合增强以及 TCF 调控基因的表达增加。 TCF 调控基因转录中与 β-连环蛋白协同作用的因素尚不明确。 TIP49 是一种 ATP 酶，之前被认为是 c-Myc 致癌转化的辅助因子，已被证明可以与 β-连环蛋白结合。我们发现，TIP49 (TIP49D302N) 的 ATPase 缺陷型突变体的表达显着抑制了 β-catenin 介导的永生化大鼠上皮细胞的肿瘤转化，以及β-catenin 失调的人结肠癌细胞的贴壁依赖性生长。 TIP49D302N 突变体抑制 β-连环蛋白介导的 TCF 依赖性细胞基因的激活。通过针对内源性 TIP49 的小干扰 RNA 方法，观察到对 β-连环蛋白/TCF 依赖性基因表达的类似抑制。 TIP49 被发现存在于与染色质重塑、组蛋白修饰因子和辅助因子的复合物中，包括 TIP60 组蛋白乙酰化酶相关蛋白反式激活/转化域相关蛋白 (TRRAP) 和 BAF53。使用染色质免疫沉淀方法，发现 TIP49、TIP60 和 TRRAP 蛋白与 TCF 依赖性细胞基因 ITF-2 基因调控区的序列相互作用。 TIP49D302N 抑制 ITF-2 基因表达的能力与 ITF-2 启动子区域 TCF 结合位点附近组蛋白乙酰化的降低有关。我们认为 TIP49 是正常和肿瘤细胞中 β-catenin/TCF 基因调节的重要辅助因子，可能在染色质重塑中发挥作用。
Beta-catenin has a key role in Wnt signaling via effects on T-cell factor (TCF)-mediated transcription. Mutational defects in beta-catenin regulation are seen in many cancers, leading to elevated beta-catenin levels, enhanced binding of beta-catenin to TCFs, and increased expression of TCF-regulated genes. Factors cooperating with beta-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 beta-catenin. We found that expression of an ATPase-deficient mutant form of TIP49 (TIP49D302N) substantially inhibited beta-catenin-mediated neoplastic transformation of immortalized rat epithelial cells and anchorage-independent growth of human colon cancer cells with deregulated beta-catenin. The TIP49D302N mutant inhibited beta-catenin-mediated activation of TCF-dependent cellular genes. Similar inhibition of the expression of beta-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 beta-catenin/TCF gene regulation in normal and neoplastic cells, likely functioning in chromatin remodeling.