Conservation of the Drosophila lateral inhibition pathway in human lung cancer: A hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression
Conservation of the Drosophila lateral inhibition pathway in human lung cancer: A hairy-related protein (HES-1) directly represses achaete-scute homolog-1 expression
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DOI：
10.1073/pnas.94.10.5355
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发表时间：
1997-05-13
影响因子：
11.1
通讯作者：
Ball, DW
中科院分区：
文献类型：
--
作者：
Chen, H;Thiagalingam, A;Ball, DW
无毛刺基因编码正常果蝇和脊椎动物神经系统发育过程中的必要转录因子。HASH1在一种具有神经内分泌(NE)特征的人肺癌-小细胞肺癌(SCLC)中有结构性表达，对与此肿瘤最相似的正常肺NE细胞的发育是必不可少的。目前，无论是在发育中的神经系统，还是在具有NE特征的正常或肿瘤细胞中，调控果蝇外的achaete-scute同源基因表达的机制都不清楚，我们现在提供的证据表明，HES-1蛋白的作用方式与其果蝇同源基因Haily相似，转录上抑制achaete-scute基因的表达，HES-1蛋白在大多数缺乏hASH1的非NE人类肺癌细胞系中大量检测到，但在表达hASH1的肺癌细胞中几乎不存在。此外，在小细胞肺癌细胞系中诱导HES-1下调内源性hASH1基因的表达。HES-1的抑制作用是通过蛋白与hASH1启动子上的C类位点结合直接实现的。因此，决定果蝇神经命运的过程中的一个关键部分在人类肺癌细胞中是保守的，此外，这一途径的调节可能是在NE肿瘤(如最致命的人类肺癌SCLC)中看到的结构性hash表达的基础。
The achaete-scute genes encode essential transcription factors in normal Drosophila and vertebrate nervous system development. Human achaete-scute homolog-1 (hASH1) is constitutively expressed in a human lung cancer with neuroendocrine (NE) features, small cell lung cancer (SCLC), and is essential for development of the normal pulmonary NE cells that most resemble this neoplasm. Mechanisms regulating achaete-scute homolog expression outside of Drosophila are presently unclear, either in the context of the developing nervous system or in normal or neoplastic cells with NE features, We now provide evidence that the protein hairy-enhancer-of-split-1 (HES-1) acts in a similar manner as its Drosophila homolog, hairy, to transcriptionally repress achaete-scute expression, HES-1 protein is detected at abundant levels in most non-NE human lung cancer cell lines which lack hASH1 but is virtually absent in hASH1-expressing lung cancer cells. Moreover, induction of HES-1 in a SCLC cell line down-regulates endogenous hASH1 gene expression. The repressive effect of HES-1 is directly mediated by binding of the protein to a class C site in the hASH1 promoter. Thus, a key part of the process that determines neural fate in Drosophila is conserved in human lung cancer cells, Furthermore, modulation of this pathway may underlie the constitutive hASH expression seen in NE tumors such as SCLC, the most virulent human lung cancer.