Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness.
Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness.
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DOI：
10.1038/onc.2010.62
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发表时间：
2010-05-20
期刊：
影响因子：
8
通讯作者：
Hughes, D. P. M.
中科院分区：
文献类型：
--
作者：
Zhang, P.;Yang, Y.;Nolo, R.;Zweidler-McKay, P. A.;Hughes, D. P. M.
高度保守的NOTCH信号通路在从果蝇到人类的多种细胞、组织和器官的发育中发挥着许多重要作用，NOTCH信号通路失调会导致多种疾病，包括血管和骨缺陷，以及几种癌症。在这里，我们描述了一种通过相互抑制两个NOTCH下游效应物：Deltex1和HES1来调节NOTCH的新机制。这一机制似乎调节骨肉瘤细胞的侵袭，因为Deltex1通过下调NOTCH/HES1信号传导抑制骨肉瘤的侵袭。内源性Deltex1对NOTCH信号的抑制作用是通过与NOTCH的胞内结构域结合以及NOTCH受体的泛素化和降解来介导的。相反，我们发现NOTCH靶基因HES1通过直接结合Deltex1的启动子导致Deltex1的转录抑制。HES1结合位点位于Deltex1转录起始位点上游400bp处。HES1介导的Deltex1的抑制需要HES1的c端H3/H4和WRPW结构域，这些结构域与TLE/Groucho共抑制子相关。综上所述，我们确定了一种在哺乳动物细胞中通过相互抑制NOTCH靶基因HES1和Deltex1来调节NOTCH信号的分子机制。这一机制可能对靶向NOTCH信号治疗骨肉瘤和其他癌症具有重要的临床意义。
The highly-conserved NOTCH signaling pathway plays many essential roles in the development of diverse cells, tissues and organs from Drosophila to humans, and dysregulated Notch signaling contributes to several disorders, including vascular and bone defects, as well as several cancers. Here we describe a novel mechanism of NOTCH regulation by reciprocal inhibition of two NOTCH downstream effectors: Deltex1 and HES1. This mechanism appears to regulate invasion of osteosarcoma cells, as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH/HES1 signaling. The inhibitory effect of endogenous Deltex1 on NOTCH signaling is mediated through binding with the intracellular domain of NOTCH and ubiquitination and degradation of NOTCH receptors. Conversely, we show that the NOTCH target gene HES1 causes transcriptional inhibition of Deltex1 by directly binding to the promoter of Deltex1. A HES1 binding site is identified 400bp upstream of the transcription start site of Deltex1. HES1-mediated repression of Deltex1 requires the C-terminal H3/H4 and WRPW domains of HES1, which associate with the TLE/Groucho corepressors. Taken together, we define a molecular mechanism regulating NOTCH signaling by reciprocal inhibition of the NOTCH target genes HES1 and Deltex1 in mammalian cells. This mechanism may have important clinical implications for targeting NOTCH signaling in osteosarcoma and other cancers.
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