SCL/TAL1 interrupting locus derepresses GLI1 from the negative control of Suppressor-of-Fused in pancreatic cancer cell
SCL/TAL1 interrupting locus derepresses GLI1 from the negative control of Suppressor-of-Fused in pancreatic cancer cell
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DOI：
10.1158/0008-5472.can-07-6661
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Ikeda, Hiroshi
中科院分区：
文献类型：
--
作者：
Kasai, Kenji;Inaguma, Shingo;Ikeda, Hiroshi
融合抑制蛋白（Suppressor-of-Fused，SUFU）作为GLI 1转录因子的物理结合蛋白，在Hedgehog（Hh）信号负调控中处于核心地位。SUFU将GLI 1束缚在细胞质中，并且在某些情况下，它与GLI 1一起移动到细胞核中，导致通过募集辅阻遏物复合物来抑制GLI 1靶基因表达。GLI 1的激活转录功能对于多种人类癌症中的细胞增殖是重要的。然而，还没有揭示GLI 1是如何从SUFU介导的抑制中去抑制的。在这里，我们显示SCL/TAL 1中断位点（SIL）产物，一种在胰腺导管腺癌（PDA）中过表达的细胞质蛋白，负责GLI 1的去抑制。我们发现SIL与SUFU的羧基末端相关，SUFU是两个不同的GLI 1结合结构域之一，这种相关性负责SUFU的细胞质束缚。过表达的SIL减弱了SUFU介导的GLI 1细胞质束缚和靶基因抑制。在PDA细胞中，SIL的敲低反过来诱导与GLI 1相关的SUFU的核积聚和GLI 1靶基因的转录抑制。重要的是，我们还发现，致癌K-RAS，而不是Sonic hedgehog，增强了SIL与SUFU氨基末端的结合，SUFU是另一个GLI 1结合结构域，导致GLI 1核转位的进一步增加。这些结果揭示了SIL在从SUFU的阴性对照中去抑制GLI 1中的作用，这是激活癌细胞中Hh信号传导的关键步骤。
As a physically binding protein of GLI1 transcription factor, Suppressor-of-Fused (SUFU) has been placed in the center of negative regulation of Hedgehog (Hh) signaling. SUFU tethers GLI1 in cytoplasm, and in some circumstances, it moves into the nucleus in association with GLI1, leading to the suppression of GLI1 target gene expression by recruiting a corepressor complex. The activated transcriptional function of GLI1 is important for cellular proliferation in a variety of human cancers. However, it has not been revealed how GLI1 is derepressed from SUFU-mediated suppression. Here, we show SCL/TAL1 interrupting locus (SIL) product, a cytoplasmic protein overexpressed in pancreatic ductal adenocarcinoma (PDA), is responsible for the derepression of GLI1. We found SIL associated with the carboxyl terminus of SUFU, one of two distinct GLI1-binding domains, and this association was responsible for cytoplasmic tethering of SUFU. Overexpressed SIL attenuated SUFU-mediated cytoplasmic tethering and target gene suppression of GLI1. Knockdown of SIL in PDA cells conversely induced the nuclear accumulation of SUFU in association with GLI1 and the transcriptional suppression of GLI1 target genes. Importantly, we also showed that oncogenic K-RAS, and not Sonic hedgehog, enhanced the SIL association with the amino-terminus of SUFU, the other GLI1-binding domain that led to further increase of nuclear translocation of GLI1. These results uncover the role of SIL in derepressing GLI1 from the negative control of SUFU, which is a crucial step for activating Hh signaling in cancer cells.