Human plastin genes. Comparative gene structure, chromosome location, and differential expression in normal and neoplastic cells.
Human plastin genes. Comparative gene structure, chromosome location, and differential expression in normal and neoplastic cells.
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DOI：
10.1016/s0021-9258(18)53842-4
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发表时间：
1993-02
期刊：
影响因子：
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通讯作者：
Ching-shwun Lin;T. Park;Zongfa Chen;J. Leavitt
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文献类型：
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作者：
Ching-shwun Lin;T. Park;Zongfa Chen;J. Leavitt
Plastins是一个在真核生物进化过程中保守的肌动蛋白结合蛋白家族，在高等真核生物的大多数组织中表达。在人类中，已经鉴定了两种普遍存在的质体异构体（L和T）。L同种型仅在造血细胞谱系中表达，而T同种型已在具有复制潜力的实体组织的所有其他正常细胞（成纤维细胞、内皮细胞、上皮细胞、黑素细胞等）中发现。然而，在许多类型的非造血来源的恶性人类细胞中发现了L-塑性蛋白，这表明其表达伴随实体组织中的肿瘤发生而被诱导。为了更多地了解plastin基因的性质及其在恶性肿瘤中的潜在作用，对L-和T- plastin基因进行了克隆和测序，以表征其结构和表达调控机制。每个基因大小约为90个碱基，由16个外显子组成。所有外显子-内含子连接序列被鉴定并显示符合典型连接序列。从它们相似的结构和编码同源性可以明显看出，这两个plastin基因是从一个共同的祖先基因分化而来的。还使用同工型特异性探针进行聚合酶链反应扩增，将L-和T-plastin基因分别定位到13号和X染色体上。对正常细胞类型和50种肿瘤细胞系的扩大调查表明，68%的癌和53%的其他非上皮来源的实体瘤表现出L-plastin表达，而正常干细胞祖细胞没有。纤维肉瘤（n = 4）、卵巢癌（n = 9）、乳腺癌（n = 4）和绒毛膜癌（n = 2）组合显示最高频率和水平的L-plastin表达（95%频率）。此外，4个肿瘤细胞系的L-plastin阴性表现出缺陷的T-plastin表达的证据，增加了与人类肿瘤发生相关的plastin异常的表观共同发病率为71%。证据支持的一个反式激活机制激活的L-质体合成伴随肿瘤的发生。还证实了伴随SV 40介导的人胚肺MRC-5成纤维细胞转化的L-plastin表达的诱导。最后，我们提出的证据表明，fimplantation是第三个不同的plastin亚型，这是专门在小肠中的高水平表达。
Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. The L isoform is expressed only in hemopoietic cell lineages, while the T isoform has been found in all other normal cells of solid tissues that have replicative potential (fibroblasts, endothelial cells, epithelial cells, melanocytes, etc.). However, L-plastin has been found in many types of malignant human cells of non-hemopoietic origin suggesting that its expression is induced accompanying tumorigenesis in solid tissues. To learn more about the nature of plastin genes and their potential role in malignancy, the L- and T- plastin genes were cloned and sequenced to characterize their structure and mechanisms of regulation of expression. Each gene was found to be approximately 90 kilobases in size and was composed of 16 exons. All exon-intron junction sequences were identified and shown to conform to the canonical junction sequences. It was evident from their similar structure and coding homology that the two plastin genes have diverged from a common ancestor gene. L- and T-plastin genes were also mapped to chromosomes 13 and X, respectively, using polymerase chain reaction amplification with isoform-specific probes. An expanded survey of normal cell types and 50 tumor cell lines, demonstrated that 68% of carcinomas and 53% of other solid tumors of nonepithelial origin exhibited L-plastin expression, whereas the normal stem cell progenitors did not. Fibrosarcomas (n = 4), ovarian carcinomas (n = 9), breast carcinomas (n = 4), and choriocarcinomas (n = 2) combined exhibited the highest frequency and levels of L-plastin expression (95% frequency). In addition, 4 tumor cell lines that were L-plastin-negative exhibited evidence of defective T-plastin expression increasing the apparent co-incidence of plastin abnormalities associated with human tumorigenesis to 71%. Evidence is presented in support of a trans-activation mechanism for activation of L-plastin synthesis accompanying tumorigenesis. The induction of L-plastin expression accompanying SV40-mediated transformation of human embryonic lung MRC-5 fibroblasts was also confirmed. Finally, we present evidence that fimbrin is a third distinct plastin isoform which is specifically expressed at high levels in the small intestine.