Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription
Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription
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DOI：
10.1128/mcb.01242-07
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发表时间：
2008-02-01
影响因子：
5.3
通讯作者：
Hiebert, Scott W.
中科院分区：
文献类型：
--
作者：
Moore, Amy C.;Amann, Joseph M.;Hiebert, Scott W.
规范 Wnt 信号传导由分子“开关”介导，该分子“开关”调节 UNA 结合蛋白 T 细胞因子 (TCF) 家族的转录特性。转录辅助抑制子的髓样易位基因 (MTG) 家族的成员经常因急性髓性白血病中的染色体易位而受到破坏，而 MTG16 可能在高达 40% 的乳腺癌中失活，MTG8 是结直肠癌的候选癌症基因。遗传学研究表明该辅阻遏物家族可能在干细胞中发挥作用。鉴于缺乏髓样易位基因相关 1 (Mtgr1) 的小鼠无法维持小肠中的分泌谱系，我们调查了可能在肠道干细胞或祖细胞中招募 Mtgr1 的转录因子，发现 MTG 家族成员与 TCF4 特异性相关。 β-连环蛋白的共表达破坏了这些辅阻遏物和 TCF4 之间的关联。此外，当在爪蟾胚胎中表达时，MTG 家族成员抑制轴形成并损害 β-连环蛋白和 XLef-1 诱导轴复制的能力，表明 MTG 家族成员在 β-连环蛋白下游发挥作用。此外，我们发现c-Myc（Wnt通路的转录靶标）在缺乏Mtgr1的小鼠小肠中过度表达，从而将Mtgr1的失活与强效癌基因的激活联系起来。
Canonical Wnt signaling is mediated by a molecular "switch" that regulates the transcriptional properties of the T-cell factor (TCF) family of UNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of beta-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited axis formation and impaired the ability of beta-catenin and XLef-1 to induce axis duplication, indicating that MTG family members act downstream of beta-catenin. Moreover, we found that c-Myc, a transcriptional target of the Wnt pathway, was overexpressed in the small intestines of mice lacking Mtgr1, thus linking inactivation of Mtgr1 to the activation of a potent oncogene.