TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP.
TGF-β drives epithelial-mesenchymal transition through δEF1-mediated downregulation of ESRP.
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DOI：
10.1038/onc.2011.493
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发表时间：
2012-06-28
期刊：
影响因子：
8
通讯作者：
Saitoh, M.
中科院分区：
文献类型：
--
作者：
Horiguchi, K.;Sakamoto, K.;Koinuma, D.;Semba, K.;Inoue, A.;Inoue, S.;Fujii, H.;Yamaguchi, A.;Miyazawa, K.;Miyazono, K.;Saitoh, M.
上皮-间质转化（EMT）是成人组织中伤口愈合、组织修复和癌症进展的关键事件。我们最近发现转化生长因子（TGF）-β诱导的EMT涉及成纤维细胞生长因子受体通过选择性剪接的同种型转换。我们在单外显子水平上进行了基于微阵列的分析，以阐明TGF-β诱导EMT过程中产生的剪接变体的变化，并发现TGF-β通过下调上皮剪接调节蛋白（ESRPs）诱导剪接模式的广泛改变。这是通过TGF-β介导的δ EF 1家族蛋白δ EF 1和SIP 1的上调实现的。在NMuMG细胞中，δ EF 1和SIP 1均通过与ESRP 2启动子结合而显著抑制ESRP 2的转录。δ EF 1和SIP 1的沉默，但不是单独的，取消TGF-β诱导的ESRP抑制。在人乳腺癌细胞系和原发肿瘤标本中，ESRPs的表达谱与δ EF 1和SIP的表达谱呈负相关。此外，在TGF-β处理的细胞中ESRP的过表达导致上皮剪接谱的恢复以及EMT的某些表型的减弱。因此，δ EF 1家族蛋白通过抑制ESRPs的表达来调节TGF-β诱导的EMT过程中的选择性剪接，从而促进乳腺癌的发生发展。
Epithelial-mesenchymal transition (EMT) is a crucial event in wound healing, tissue repair and cancer progression in adult tissues. We have recently shown that transforming growth factor (TGF)-β-induced EMT involves isoform switching of fibroblast growth factor receptors by alternative splicing. We performed a microarray-based analysis at single exon level to elucidate changes in splicing variants generated during TGF-β-induced EMT, and found that TGF-β induces broad alteration of splicing patterns by downregulating epithelial splicing regulatory proteins (ESRPs). This was achieved by TGF-β-mediated upregulation of δEF1 family proteins, δEF1 and SIP1. δEF1 and SIP1 each remarkably repressed ESRP2 transcription through binding to the ESRP2 promoter in NMuMG cells. Silencing of both δEF1 and SIP1, but not either alone, abolished the TGF-β-induced ESRP repression. The expression profiles of ESRPs were inversely related to those of δEF1 and SIP in human breast cancer cell lines and primary tumor specimens. Further, overexpression of ESRPs in TGF-β-treated cells resulted in restoration of the epithelial splicing profiles as well as attenuation of certain phenotypes of EMT. Therefore, δEF1 family proteins repress the expression of ESRPs to regulate alternative splicing during TGF-β-induced EMT and the progression of breast cancers.
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影响因子：
2.7
作者：
Hoshino, Yukari;Katsuno, Yoko;Miyazono, Kohei
通讯作者：
Miyazono, Kohei
影响因子：
5.8
作者：
Lee, Bongshin;Brown, Kristy;Seo, Jinwook
通讯作者：
Seo, Jinwook
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
11.4
作者：
Warzecha, Claude C.;Jiang, Peng;Carstens, Russ P.
通讯作者：
Carstens, Russ P.
DOI：
10.2183/pjab.85.314
发表时间：
2009
期刊：
Proceedings of the Japan Academy. Series B, Physical and biological sciences
影响因子：
--
作者：
Miyazono K
通讯作者：
Miyazono K