The human Rgr oncogene is overexpressed in T-cell malignancies and induces transformation by acting as a GEF for Ras and Ral.
The human Rgr oncogene is overexpressed in T-cell malignancies and induces transformation by acting as a GEF for Ras and Ral.
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DOI：
10.1038/onc.2011.93
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发表时间：
2011-08-25
期刊：
影响因子：
8
通讯作者：
Pellicer, A.
中科院分区：
文献类型：
--
作者：
Osei-Sarfo, K.;Martello, L.;Ibrahim, S.;Pellicer, A.
GTPases的Ras超家族参与了许多细胞过程的修饰，包括细胞运动、增殖和分化。我们的实验室之前已经在dba诱导的兔鳞状细胞癌及其人类同源物hRgr中发现了RalGDS相关（Rgr）癌基因。在本研究中，我们分析了人类hRgr转录物在一组人类造血恶性肿瘤中的表达水平，发现截断形式（疾病截断；dr - hRgr）在许多t细胞源性肿瘤中显着过表达。虽然Rgr原癌基因属于鸟嘌呤核苷酸交换因子（GEFs）的RalGDS家族，但我们发现，在将hRgr引入成纤维细胞系后，它能够引发Ral和Ras gtpase的激活。此外，体外鸟嘌呤核苷酸交换实验证实，hRgr通过GDP解离促进Ral和Ras的激活，这是GEF蛋白的一个关键特征。hRgr对两种小gtpase都具有鸟嘌呤核苷酸交换活性，当在该蛋白的催化结构域（CDC25）内进行点突变（cd） Dtr-hRgr时，这种活性降低。这些观察结果促使对hRgr和（cd） hRgr在培养细胞中的表达的生物学效应进行分析。在这里，我们发现hRgr在低血清中增加增殖，增加侵袭，减少锚定依赖性，并促进细胞周期进入S期；在催化死突变体的存在下被废除或严重降低的特性。我们得出结论，hRgr激活Ral和Ras的能力是其转化诱导表型的原因，它可能是一些T细胞恶性肿瘤发展的重要贡献者。
The Ras superfamily of GTPases is involved in the modification of many cellular processes including cellular motility, proliferation and differentiation. Our laboratory has previously identified the RalGDS related (Rgr) oncogene in a DMBA-induced rabbit squamous cell carcinoma and its human orthologue, hRgr. In the present study, we analyzed the expression levels of the human hRgr transcript in a panel of human hematopoietic malignancies and found that a truncated form (diseased-truncated; Dtr-hrgr) was significantly overexpressed in many T-cell derived neoplasms. Although the Rgr proto-oncogene belongs to the RalGDS family of guanine nucleotide exchange factors (GEFs), we show that upon the introduction of hRgr into fibroblast cell lines it is able to elicit the activation of both Ral and Ras GTPases. Moreover, in vitro guanine nucleotide exchange assays confirm that hRgr promotes Ral and Ras activation through GDP dissociation, which is a critical characteristic of GEF proteins. hRgr has guanine nucleotide exchange activity for both small GTPases and this activity was reduced when a point mutation within the catalytic domain (CDC25) of the protein, (cd) Dtr-hRgr, was utilized. These observations prompted the analysis of the biological effects of hRgr and (cd) hRgr expression in cultured cells. Here, we show that hRgr increases proliferation in low serum, increases invasion, reduces anchorage dependence, and promotes the progression into S phase of the cell cycle; properties that are abolished or severely reduced in the presence of the catalytic dead mutant. We conclude that the ability of hRgr to activate both Ral and Ras is responsible for its transformation-inducing phenotype and it could be an important contributor in the development of some T cell malignancies.
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