The Zinc Fingers and Homeoboxes (Zhx) proteins, Zhx1, Zhx2, and Zhx3, comprise a small family of proteins containing two amino-terminal C2-H2 zinc fingers and four or five carboxy-terminal homeodomains. These multiple homeodomains make Zhx proteins unusual because the majority of homeodomain-containing proteins contain a single homeodomain. Studies in cultured cells and mice suggest that Zhx proteins can function as positive or negative transcriptional regulators. Zhx2 regulates numerous hepatic genes, and all three Zhx proteins have been implicated in different cancers. Because Zhx proteins contain multiple predicted homeodomains, are associated with interesting physiological traits, and seem to be only present in the vertebrate lineage, we investigated the evolutionary history of this small family by comparing Zhx homologs from a wide range of chordates. This analysis indicates that the zinc finger motifs and homeodomains are highly similar among all Zhx proteins and also identifies additional Zhx-specific conserved regions, including a 13 amino acid amino-terminal motif that is nearly identical among all gnathostome Zhx proteins. We found single Zhx proteins in the sea lamprey (Petromyzon marinus) and in the nonvertebrate chordates sea squirt (Ciona intestinalis) and lancelet (Branchiostoma floridae); these Zhx proteins are most similar to gnathostome Zhx3. Based on our analyses, we propose that a duplication of the primordial Zhx gene gave rise to Zhx3 and the precursor to Zhx1 and Zhx2. A subsequent tandem duplication of this precursor generated Zhx1 and Zhx2 found in gnathostomes.

中文翻译：

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锌指和同源盒蛋白家族的进化分析确定了多个保守域和一个共同的早期柠檬酸盐祖先。

锌指和同源盒（Zhx）蛋白Zhx1，Zhx2和Zhx3包含一小类蛋白质，其中包含两个氨基端C2-H2锌指和四个或五个羧基端同源域。这些多数同源域使Zhx蛋白与众不同，因为大多数含同源域的蛋白质都包含一个同源域。在培养的细胞和小鼠中的研究表明Zhx蛋白可以充当正转录或负转录调节因子。Zhx2调节许多肝脏基因，并且所有三种Zhx蛋白都与不同的癌症有关。由于Zhx蛋白包含多个预测的同源域，与有趣的生理特征相关，并且似乎仅存在于脊椎动物谱系中，我们通过比较来自各种和弦的Zhx同源物，研究了这个小家族的进化史。该分析表明锌指基序和同源域在所有Zhx蛋白之间高度相似，并且还鉴定了其他Zhx特异性保守区，包括在所有gnathostome Zhx蛋白中几乎相同的13个氨基酸的氨基酸末端基序。我们在海七rey鱼（Petromyzon marinus）和非脊椎动物的脊索海鞘（Ciona intestinalis）和长矛（lancelet）中发现了单一的Zhx蛋白；佛罗里达州的Branchiostoma。这些Zhx蛋白与gnathostome Zhx3最相似。根据我们的分析，我们建议原始Zhx基因的重复产生Zhx3以及Zhx1和Zhx2的前体。