The tissue-dependent keratin 19 gene transcription is regulated by GKLF/KLF4 and Sp1.
The tissue-dependent keratin 19 gene transcription is regulated by GKLF/KLF4 and Sp1.
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DOI：
10.1074/jbc.m004013200
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发表时间：
2000-09
期刊：
影响因子：
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通讯作者：
F. Brembeck;Anil K. Rustgi
中科院分区：
文献类型：
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作者：
F. Brembeck;Anil K. Rustgi
角蛋白在细胞分化和细胞骨架组织中起关键作用。角蛋白19 （K19）是独特的，因为它被认为是一些组织（如皮肤中的毛囊）中干细胞的标记物。它也与食管癌和胰腺癌的恶性转化有关。在这里，我们发现K19启动子在来自食道和胰腺的胃肠道癌细胞亚群中活跃，但在其他情况下不活跃。这种活性被定位到一个短区域，该区域含有富含肠道的kr<s:1> ppel样因子（GKLF/KLF4）和Sp1的重叠结合位点。GKLF具有较高的结合亲和力，是Sp-1蛋白水平低的细胞中主要的结合因子。胰腺腺泡细胞通常不表达K19，但GKLF和Sp1在这些细胞中过表达导致异常表达，与胰腺癌中观察到的情况相似。这些结果表明，普遍存在的转录因子和组织限制性转录因子在决定组织和肿瘤特异性基因表达模式方面的功能相互作用。
Keratins play critical roles in cellular differentiation and cytoskeletal organization. Keratin 19 (K19) is unique because it has been implicated as a marker of stem cells in some tissues, such as the hair follicle in the skin. It is also associated with malignant transformation in esophageal and pancreatic cancers. Here, we show that the K19 promoter is active in a subset of gastrointestinal cancer cells derived from esophageal and pancreas but inactive in other contexts. This activity was mapped to a short region containing an overlapping binding site for gut-enriched Krüppel-like factor (GKLF/KLF4) and Sp1. GKLF has a higher binding affinity and is the predominant binding factor in cells with low Sp-1 protein levels. Pancreatic acinar cells normally do not express K19, but overexpression of GKLF and Sp1 in these cells leads to aberrant expression, similar to what is observed in pancreatic cancer. These results demonstrate the functional interaction of ubiquitous and tissue-restricted transcription factors in determining tissue- and neoplasm-specific patterns of gene expression.