IMP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer.
IMP3 Stabilization of WNT5B mRNA Facilitates TAZ Activation in Breast Cancer.
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DOI：
10.1016/j.celrep.2018.04.113
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发表时间：
2018-05-29
期刊：
影响因子：
8.8
通讯作者：
Mercurio AM
中科院分区：
文献类型：
--
作者：
Samanta S;Guru S;Elaimy AL;Amante JJ;Ou J;Yu J;Zhu LJ;Mercurio AM
胰岛素样生长因子-2 mRNA结合蛋白3（IMP3）是一种与许多侵袭性癌症相关的癌胚蛋白，并与乳腺癌干细胞（CSC）的功能有关。然而，对所涉及的机制知之甚少。我们观察到IMP3促进TAZ的激活，TAZ是Hippo信号传导的转录共激活因子，对于乳腺CSC的功能是必需的。IMP 3激活TAZ的机制涉及mRNA稳定性和转录调控。IMP 3通过抑制靶向WNT 5 B的miR 145 - 5 p间接稳定替代WNT配体（WNT 5 B）的mRNA，从而通过替代WNT信号传导激活TAZ。IMP 3还通过也由WNT 5 B介导的机制促进SLUG的转录，这是TAZ核定位和活化所必需的。这些结果表明，TAZ可以通过mRNA结合蛋白进行调节，并且这种调节涉及Hippo和替代WNT信号通路的整合。调节TAZ的机制对于理解生物学和改善乳腺癌和其他癌症的治疗至关重要。Samanta等人证明，胰岛素样生长因子-2 mRNA结合蛋白3（IMP 3）通过稳定WNT 5 B mRNA和促进替代Wnt信号传导，有助于乳腺癌干细胞中的TAZ活化。IMP3和WNT 5 B还共同起作用以促进SLUG的转录，这是TAZ核定位和活化所必需的。
Insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) is an oncofetal protein associated with many aggressive cancers and implicated in the function of breast cancer stem cells (CSCs). The mechanisms involved, however, are poorly understood. We observed that IMP3 facilitates the activation of TAZ, a transcriptional co-activator of Hippo signaling that is necessary for the function of breast CSCs. The mechanism by which IMP3 activates TAZ involves both mRNA stability and transcriptional regulation. IMP3 stabilizes the mRNA of an alternative WNT ligand (WNT5B) indirectly by repressing miR145-5p, which targets WNT5B, resulting in TAZ activation by alternative WNT signaling. IMP3 also facilitates the transcription of SLUG, which is necessary for TAZ nuclear localization and activation, by a mechanism that is also mediated by WNT5B. These results demonstrate that TAZ can be regulated by an mRNA-binding protein and that this regulation involves the integration of Hippo and alternative WNT-signaling pathways. Mechanisms that regulate TAZ are critical for understanding the biology and improving the therapy of breast and other cancers. Samanta et al. demonstrate that insulin-like growth factor-2 mRNA-binding protein 3 (IMP3) contributes to TAZ activation in breast cancer stem cells by stabilizing WNT5B mRNA and facilitating alternative Wnt signaling. IMP3 and WNT5B also function together to promote the transcription of SLUG, which is necessary for TAZ nuclear localization and activation.
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影响因子：
7.3
作者：
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DOI：
10.1073/pnas.1701464114
发表时间：
2017-03-21
影响因子：
11.1
作者：
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通讯作者：
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