HOXC13 is involved in the regulation of human hair keratin gene expression
HOXC13 is involved in the regulation of human hair keratin gene expression
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DOI：
10.1074/jbc.m101616200
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发表时间：
2002-02-01
影响因子：
4.8
通讯作者：
Schweizer, J
中科院分区：
文献类型：
--
作者：
Jave-Suarez, LF;Winter, H;Schweizer, J
目前，HOXC13是HOX多基因家族中唯一的成员，当突变或在小鼠中过度表达时会产生脆弱的毛发表型。为了确定毛发角蛋白基因是否是该转录因子的靶标，我们分析了人发角蛋白基因的HOXC13反应性，其表达与核HOXC13的表达一致，免疫显示在人生长期毛囊下部毛发形成室的细胞中。我们发现，HOXC13，而不是同源盒缺失的HOXC13，强烈激活了基因的启动子，相应的近端启动子区域足以进行最佳激活。毛发角蛋白启动子含有许多可能的HOX结合核心基序TAT、TTAT和TTAC。电泳迁移率改变分析表明，HOXC13与明显集中在近端启动子区域的不同的TAT和TTAT核心基序结合。对HOXC13结合和非结合核心基序两侧的序列进行比较，可以推导出扩展的8bp HOXC13共同结合序列TT(A/F)ATNPuPu。因此，HOXC13的DNA结合条件不同于其他类似组13的成员，即小鼠HOXB13和Hoxd13，先前的研究得到了一致的结合序列TTFA(T/C)NPuPu。总而言之，我们的数据表明HOXC13直接参与了毛发角蛋白在毛细胞分化早期的表达控制。
At present, HOXC13 is the only member of the HOX multigene family that produces a fragile hair phenotype when mutated or overexpressed in mice. To determine whether hair keratin genes are targets for this transcription factor, we analyzed the HOXC13 responsiveness of human hair keratin genes, whose expression matched that of nuclear HOXC13, immunologically revealed in cells of the lower hair-forming compartment of the human anagen hair follicle. We show that HOXC13, but not a homeobox-deleted HOXC13, strongly activated the promoters of the genes, with the respective proximal promoter regions being sufficient for optimal activation. The hair keratin promoters contained numerous putative Hox binding core motifs TAAT, TTAT, and TTAC. Electrophoretic mobility shift assays revealed that HOXC13 bound exclusively to distinct TAAT and TTAT core motifs that were clearly concentrated in the proximal promoter regions. A comparison of the sequences flanking HOXC13 binding and nonbinding core motifs, respectively, allowed the deduction of an extended 8-bp HOXC13 consensus binding sequence TT(A/F)ATNPuPu. Thus, the DNA binding conditions for HOXC13 were distinct from those of other members of the paralogous group 13, i.e. murine Hoxb13 and HOXd13, for which previous investigations yielded the consensus binding sequence TTFA(T/C)NPuPu. Collectively, our data speak for a direct involvement of HOXC13 in the control of hair keratin expression during early trichocyte differentiation.