Divergent C-terminal transactivation domains of Rel/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes
Divergent C-terminal transactivation domains of Rel/NF-κB proteins are critical determinants of their oncogenic potential in lymphocytes
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DOI：
10.1038/sj.onc.1207221
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发表时间：
2004-02-05
期刊：
影响因子：
8
通讯作者：
Gélinas, C
中科院分区：
文献类型：
--
作者：
Fan, YJ;Rayet, B;Gélinas, C
rel/nf-kappaB基因在许多人造血系统肿瘤中扩增、过表达或组成性激活;然而，它们促进肿瘤发生的分子机制仍有待确定。在这里，我们探讨了细胞Rel/NF-κ B蛋白在体外和体内的致癌潜力。我们发现野生型小鼠和人类c-rel基因的过度表达足以在严格的软琼脂试验中恶性转化原代脾细胞，并在体内产生致命的肿瘤。相反，relA和IKK β的组成型活性形式则没有。重要的是，一个杂合RelA蛋白与其C-末端的反式激活结构域取代的v-Rel在体外和体内是潜在的致癌性。v-Rel的反式激活结构域选择性地赋予RelA的Rel同源结构域（RHD）致癌表型，但不赋予p50/NF-κ B1、p52/NF-κ B2或RelB的更趋异的RHD。总的来说，我们的研究结果突出了哺乳动物c-Rel和RelA蛋白质内在致癌活性的重要差异，并表明其差异致癌性的关键决定因素位于其不同的反式激活结构域。这些发现为哺乳动物Rel/NF-κ B因子在体内动物模型中白血病/淋巴瘤发生中的作用提供了实验证据，并且与c-rel在许多人类淋巴瘤中的意义一致。
rel/nf-kappaB genes are amplified, overexpressed, or constitutively activated in many human hematopoietic tumors; however, the molecular mechanisms by which they contribute to tumorigenesis remain to be determined. Here, we explored the oncogenic potential of cellular Rel/NF-kappaB proteins in vitro and in vivo. We show that overexpression of wild-type mouse and human c-rel genes suffices to malignantly transform primary spleen cells in stringent soft agar assays and produce fatal tumors in vivo. In contrast relA and a constitutively active form of IKKbeta did not. Importantly, a hybrid RelA protein with its C-terminal transactivation domain substituted by that of v-Rel was potently oncogenic in vitro and in vivo. The transactivation domain of v-Rel selectively conferred an oncogenic phenotype upon the Rel homology domain (RHD) of RelA, but not to the more divergent RHDs of p50/NF-kappaB1, p52/NF-kappaB2, or RelB. Collectively, our results highlight important differences in the intrinsic oncogenic activity of mammalian c-Rel and RelA proteins, and indicate that critical determinants of their differential oncogenicity reside in their divergent transactivation domains. These findings provide experimental evidence for a role of mammalian Rel/NF-kappaB factors in leukemia/lymphomagenesis in an in vivo animal model, and are consistent with the implication of c-rel in many human lymphomas.