Aberrant function of the Ras-related protein TC21/R-Ras2 triggers malignant transformation.
Aberrant function of the Ras-related protein TC21/R-Ras2 triggers malignant transformation.
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Ras 相关蛋白 TC21/R-Ras2 的功能异常会引发恶性转化。
DOI：
10.1128/mcb.14.6.4108-4115.1994
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发表时间：
1994
影响因子：
5.3
通讯作者：
Der,CJ
中科院分区：
文献类型：
--
作者：
Graham,SM;Cox,AD;Drivas,G;Rush,MG;D'Eustachio,P;Der,CJ
尽管人类 Ras 蛋白是 Ras 相关蛋白大超家族的成员，但迄今为止，只有三种哺乳动物 Ras 基因编码的蛋白被发现具有致癌潜力。在已知的 Ras 相关蛋白中，TC21/R-Ras2 与 Ras 蛋白表现出最显着的氨基酸同一性 (55%)。我们已经生成了 TC21 的突变形式，其具有类似于激活 Ras 致癌潜力的氨基酸取代 [指定为 TC21(22V) 和 TC21(71L)]，并在 NIH 3T3 和 Rat-1 转化测定中将 TC21 的生物学特性与 Ras 蛋白的生物学特性进行了比较。虽然野生型TC21在体外没有显示出任何转化潜力，但TC21(22V)和TC21(71L)都显示出令人惊讶的有效转化活性，可与致癌Ras蛋白的强转化活性相媲美。与Ras转化细胞一样，表达突变TC21蛋白的NIH 3T3细胞在单层培养物中形成形态转化细胞的病灶，在低血清中增殖，在软琼脂中形成集落，并在裸鼠中形成进行性肿瘤。因此，TC21 是第一个表现出与 Ras 相当的有效转化活性的 Ras 相关蛋白。此外，突变的 TC21 蛋白还刺激丝裂原激活蛋白激酶的组成型激活以及 Ras 响应启动子元件（Ets/AP-1 和 NF-kB）的转录激活。我们得出的结论是，异常的 TC21 功能可能通过类似于致癌 Ras 的信号转导途径触发细胞转化，并表明 TC21 活性失调可能对人类肿瘤发生有重大贡献。
Although the human Ras proteins are members of a large superfamily of Ras-related proteins, to date, only the proteins encoded by the three mammalianrasgenes have been found to possess oncogenic potential. Among the known Ras-related proteins, TC21/R-Ras2 exhibits the most significant amino acid identity (55%) to Ras proteins. We have generated mutant forms of TC21 that possess amino acid substitutions analogous to those that activate Ras oncogenic potential [designated TC21(22V) and TC21(71L)] and compared the biological properties of TC21 with those of Ras proteins in NIH 3T3 and Rat-1 transformation assays. Whereas wild-type TC21 did not show any transforming potential in vitro, both TC21(22V) and TC21(71L) displayed surprisingly potent transforming activities that were comparable to the strong transforming activity of oncogenic Ras proteins. Like Ras-transformed cells, NIH 3T3 cells expressing mutant TC21 proteins formed foci of morphologically transformed cells in monolayer cultures, proliferated in low serum, formed colonies in soft agar, and developed progressive tumors in nude mice. Thus, TC21 is the first Ras-related protein to exhibit potent transforming activity equivalent to that of Ras. Furthermore, mutant TC21 proteins also stimulated constitutive activation of mitogen-activated protein kinases as well as transcriptional activation from Ras-responsive promoter elements (Ets/AP-1 and NF-kB). We conclude that aberrant TC21 function may trigger cellular transformation via a signal transduction pathway similar to that of oncogenic Ras and suggest that deregulated TC21 activity may contribute significantly to human oncogenesis.