Direct Regulation of Alternative Splicing by SMAD3 through PCBP1 Is Essential to the Tumor-Promoting Role of TGF-β.
Direct Regulation of Alternative Splicing by SMAD3 through PCBP1 Is Essential to the Tumor-Promoting Role of TGF-β.
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DOI：
10.1016/j.molcel.2016.09.013
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发表时间：
2016-11-03
期刊：
影响因子：
16
通讯作者：
Zhang, Ying E.
中科院分区：
文献类型：
--
作者：
Tripathi, Veenu;Sixt, Katherine M.;Gao, Shaojian;Xu, Xuan;Huang, Jing;Weigert, Roberto;Zhou, Ming;Zhang, Ying E.
在癌症的晚期阶段，TGF-β与来自受体酪氨酸激酶途径的输入一起促进肿瘤进展。然而，支持信号合作并将TGF-β从有效的生长抑制剂转化为肿瘤促进剂的机制尚未完全了解。我们在这里报告，TGF-β通过SMAD 3介导的磷酸化T179与RNA结合蛋白PCBP 1的相互作用直接调节癌症干细胞标志物CD 44的选择性剪接。我们发现TGF-β和EGF分别诱导SMAD 3和PCBP 1共定位于SC 35阳性核斑点中，并且这两种蛋白在CD 44前体mRNA的可变外显子区相互作用以抑制剪接体组装，从而有利于表达间充质亚型CD 44 s而不是上皮亚型CD 44 E。我们进一步表明，SMAD 3介导的选择性剪接对TGF-β的肿瘤促进作用至关重要，并对有助于上皮向间质转化和转移的基因的蛋白质产物具有全局影响。SMAD是TGF-β途径的已知转录因子。Tripathi等人在此报道，SMAD 3还通过与RNA结合蛋白PCBP 1的伙伴关系直接调节选择性剪接，这种调节对于TGF-β的肿瘤促进作用至关重要。
In advanced stages of cancers, TGF-β promotes tumor progression in conjunction with inputs from receptor tyrosine kinase pathways. However, mechanisms that underpin the signaling cooperation and convert TGF-β from a potent growth inhibitor to a tumor promoter are not fully understood. We report here that TGF-β directly regulates alternative splicing of cancer stem cell marker CD44 through a phosphorylated T179 of SMAD3-mediated interaction with RNA-binding protein PCBP1. We show that TGF-β and EGF respectively induce SMAD3 and PCBP1 to colocalize in SC35 positive nuclear speckles, and the two proteins interact in the variable exon region of CD44 pre-mRNA to inhibit spliceosome assembly in favor of expressing the mesenchymal isoform CD44s over the epithelial isoform CD44E. We further show that the SMAD3-mediated alternative splicing is essential to the tumor-promoting role of TGF-β and has a global influence on protein products of genes instrumental to epithelial to mesenchymal transition and metastasis. SMADs are known transcription factors of the TGF-β pathway. Tripathi et al report here that SMAD3 also directly regulates alternative splicing through a partnership with RNA binding protein PCBP1 and this regulation is essential to the tumor-promoting role of TGF-β.
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影响因子：
8
作者：
Horiguchi, K.;Sakamoto, K.;Koinuma, D.;Semba, K.;Inoue, A.;Inoue, S.;Fujii, H.;Yamaguchi, A.;Miyazawa, K.;Miyazono, K.;Saitoh, M.
通讯作者：
Saitoh, M.
DOI：
10.1073/pnas.0701065104
发表时间：
2007-04-03
影响因子：
11.1
作者：
Meng, Qingchang;Rayala, Suresh K.;Kumar, Rakesh
通讯作者：
Kumar, Rakesh
影响因子：
21.3
作者：
Inui, Masafumi;Manfrin, Andrea;Piccolo, Stefano
通讯作者：
Piccolo, Stefano
影响因子：
15.9
作者：
Brown, Rhonda L.;Reinke, Lauren M.;Cheng, Chonghui
通讯作者：
Cheng, Chonghui
影响因子：
3.7
作者：
Vervoort SJ;Lourenço AR;van Boxtel R;Coffer PJ
通讯作者：
Coffer PJ