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首页> 外文期刊>The EMBO journal. >TGIF1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma
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TGIF1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma

机译：TGIF1作为一个肿瘤抑制功能胰腺导管腺癌

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A prominent function of TGIF1 is suppression of transforming growth factor beta (TGF-beta) signaling, whose inactivation is deemed instrumental to the progression of pancreatic ductal adenocarcinoma (PDAC), as exemplified by the frequent loss of the tumor suppressor gene SMAD4 in this malignancy. Surprisingly, we found that genetic inactivation of Tgif1 in the context of oncogenic Kras, Kras(G12D), culminated in the development of highly aggressive and metastatic PDAC despite de-repressing TGF-beta signaling. Mechanistic experiments show that TGIF1 associates with Twist1 and inhibits Twist1 expression and activity, and this function is suppressed in the vast majority of human PDACs by Kras(G12D)/MAPK-mediated TGIF1 phosphorylation. Ablating Twist1 in Kras(G12D);Tgif1(KO) mice completely blunted PDAC formation, providing the proof-of-principle that TGIF1 restrains Kras(G12D)-driven PDAC through its ability to antagonize Twist1. Collectively, these findings pinpoint TGIF1 as a potential tumor suppressor in PDAC and further suggest that sustained activation of TGF-beta signaling might act to accelerate PDAC progression rather than to suppress its initiation.
机译：著名的函数TGIF1镇压转化生长因子β(及)信号,其失活被认为是仪器对胰腺癌的进展导管腺癌(PDAC),作为例证频繁的肿瘤抑制基因SMAD4的恶性肿瘤。基因失活的Tgif1上下文致癌的喀斯特,喀斯特(G12D),达到高潮高度积极的发展和转移PDAC尽管de-repressing及信号。机械的实验表明,TGIF1同事Twist1和抑制Twist1表达和活动,这个函数抑制在绝大多数人类PDACs喀斯特(G12D) / MAPK-mediated TGIF1磷酸化。去除Twist1在喀斯特(G12D); Tgif1 (KO)老鼠完全钝化PDAC的形成,提供了理论水平,TGIF1抑制喀斯特(G12D)简况PDAC通过其能力对抗Twist1。查明TGIF1作为潜在的肿瘤抑制PDAC,进一步表明,持续激活及信号可能会采取行动加速PDAC进展而不是抑制它的起始。

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