TGIF inhibits retinoid signaling
TGIF inhibits retinoid signaling
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DOI：
10.1128/mcb.26.3.990-1001.2006
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发表时间：
2006-02-01
影响因子：
5.3
通讯作者：
Wotton, D
中科院分区：
文献类型：
--
作者：
Bartholin, L;Powers, SE;Wotton, D
TGIF（TG相互作用因子）抑制转化生长因子P（TGF-β）激活的基因表达，并可通过特定的类维生素A反应元件抑制转录。人类TGIF的突变与前脑无裂畸形有关，前脑无裂畸形是一种由遗传和环境原因引起的颅面发育严重缺陷。TGF-β和视黄酸信号都与颅面发育有关。在这里，我们分析了TGIF在调节类维生素A反应基因表达中的作用。我们证明TGIF与RXR α类视色素受体的配体结合域相互作用，并抑制类视色素反应元件的转录。TGIF募集一般辅阻遏物CtBP至RXR α，并且这种募集是TGIF完全阻遏所需的。TGIF和RXR α之间的相互作用通过加入视黄酸而降低，这与TGIF作为RXR α转录辅抑制因子的作用一致。我们在小鼠中创建了Tgif无效突变，并测试了突变小鼠对增加维甲酸水平的敏感性。Tgif突变体胚胎对维甲酸诱导的致畸作用更敏感，Tgif缺失小鼠的组织中类维生素A靶基因表达水平更高。这些结果表明TGIF作为转录辅抑制因子的重要作用，其通过视黄酸调节发育信号，并提高了TGIF可能抑制其他RXR依赖性转录反应的可能性。
TGIF (TG-interacting factor) represses transforming growth factor P (TGF-beta)-activated gene expression and can repress transcription via a specific retinoid response element. Mutations in human TGIF are associated with holoprosencephaly, a severe defect of craniofacial development with both genetic and environmental causes. Both TGF-beta and retinoic acid signaling are implicated in craniofacial development. Here, we analyze the role of TGIF in regulating retinoid responsive gene expression. We demonstrate that TGIF interacts with the ligand binding domain of the RXR alpha retinoid receptor and represses transcription from retinoid response elements. TGIF recruits the general corepressor, CtBP, to RXR alpha, and this recruitment is required for full repression by TGIF. Interaction between TGIF and RXR alpha is reduced by the addition of retinoic acid, consistent with a role for TGIF as an RXR alpha transcriptional corepressor. We created a Tgif null mutation in mice and tested the sensitivity of mutant mice to increased levels of retinoic acid. Tgif mutant embryos are more sensitive to retinoic acid-induced teratogenesis, and retinoid target genes are expressed at a higher level in tissues from Tgif null mice. These results demonstrate an important role for TGIF as a transcriptional corepressor, which regulates developmental signaling by retinoic acid, and raises the possibility that TGIF may repress other RXR-dependent transcriptional responses.