Structure, expression, and function of human pituitary tumor-transforming gene (PTTG)
Structure, expression, and function of human pituitary tumor-transforming gene (PTTG)
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DOI：
10.1210/me.13.1.156
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发表时间：
1999-01-01
影响因子：
--
通讯作者：
Melmed, S
中科院分区：
文献类型：
--
作者：
Zhang, X;Horwitz, GA;Melmed, S
尽管在描述垂体肿瘤的病理生理学和遗传学方面取得了进展，但对其发病机制的分子机制仍知之甚少。最近，我们从大鼠垂体肿瘤细胞中分离出了一个转化基因【垂体瘤转化基因（PTTG）】。在这里，我们描述了人类 PTTG 的克隆，它位于染色体 5q33 上，与其大鼠对应物具有惊人的序列同源性。 Northern 分析显示 PTTG 在正常成人睾丸、胸腺、结肠、小肠、脑、肺和胎儿肝脏中表达，但在几种癌细胞系中观察到最丰富的 PTTG mRNA 水平。用人 PTTG cDNA 稳定转染 NIH 3T3 细胞，在体外引起不依赖贴壁的转化，并在将转染子注射到无胸腺小鼠体内时诱导体内肿瘤形成。转染的 NIH 3T3 细胞中 PTTG 的过度表达还刺激碱性成纤维细胞生长因子（一种人垂体肿瘤生长调节因子）的表达和分泌。在 PTTG 蛋白序列中检测到富含脯氨酸的区域，其中包含两个用于 SH3 结构域结合位点的 PXXP 基序。当通过定点诱变改变这些脯氨酸残基时，PTTG的体外转化和体内肿瘤诱导活性以及碱性成纤维细胞生长因子的刺激被消除。这些结果表明人类PTTG（一种脐癌基因）可能通过SH3介导的信号转导途径和生长因子的激活发挥作用。
Despite advances in characterizing the pathophysiology and genetics of pituitary tumors, molecular mechanisms of their pathogenesis are poorly understood. Recently, we isolated a transforming gene [pituitary tumor-transforming gene (PTTG)] from rat pituitary tumor cells. Here we describe the cloning of human PTTG, which is located on chromosome 5q33 and shares striking sequence homology with its rat counterpart. Northern analysis revealed PTTG expression in normal adult testis, thymus, colon, small intestine, brain, lung, and fetal liver, but most abundant levels of PTTG mRNA were observed in several carcinoma cell lines. Stable transfection of NIH 3T3 cells with human PTTG cDNA caused anchorage-independent transformation in vitro and induced in vivo tumor formation when transfectants were injected into athymic mice. Overexpression of PTTG in transfected NIH 3T3 cells also stimulated expression and secretion of basic fibroblast growth factor, a human pituitary tumor growth-regulating factor. A proline-rich region, which contains two PXXP motifs for the SH3 domain-binding site, was detected in the PTTG protein sequence. When these proline residues were changed by site-directed mutagenesis, PTTG in vitro transforming and in vivo tumor-inducing activity, as well as stimulation of basic fibroblast growth factor, was abrogated. These results indicate that human PTTG, a navel oncogene, may function through SH3-mediated signal transduction pathways and activation of growth factor(s).