Dual Roles for NFAT Transcription Factor Genes as Oncogenes and Tumor Suppressors
Dual Roles for NFAT Transcription Factor Genes as Oncogenes and Tumor Suppressors
复制标题
DOI：
10.1128/mcb.00256-08
复制
发表时间：
2008-12-01
影响因子：
5.3
通讯作者：
Viola, Joao P. B.
中科院分区：
文献类型：
--
作者：
Robbs, Bruno K.;Cruz, Andre L. S.;Viola, Joao P. B.
活化T细胞核因子（NFAT）首先被描述为淋巴细胞中的活化和分化转录因子。一些体外研究表明 NFAT 家族成员是多余的蛋白质。然而，对 NFAT 蛋白缺陷小鼠的分析表明，NFAT 转录因子家族在细胞增殖和凋亡的调节中发挥着不同的作用。 NFAT 还可以调节影响肿瘤生长和存活的多种细胞周期和存活因素。在这里，我们证明 NFAT 蛋白的两种组成型活性形式（CA-NFAT1 和 CA-NFAT2 短亚型）在 NIH 3T3 细胞中诱导不同的表型。 CA-NFAT1 表达会诱导 NIH 3T3 成纤维细胞的细胞周期停滞和细胞凋亡，而 CA-NFAT2 短亚型会导致增殖能力增加并诱导细胞转化。此外，NFAT1缺陷的小鼠表现出化学致癌物诱导的肿瘤形成的倾向增加，并且CA-NFAT1的表达破坏了H-rasV12癌基因诱导的NIH 3T3细胞的转化。 NFAT1 的不同作用至少部分归因于蛋白质 C 末端结构域。这些结果表明，NFAT1 基因充当肿瘤抑制基因，而 NFAT2 短亚型基因充当癌基因，支持这两种转录因子在肿瘤发展中的不同作用。
Nuclear factor of activated T cells (NFAT) was first described as an activation and differentiation transcription factor in lymphocytes. Several in vitro studies suggest that NFAT family members are redundant proteins. However, analysis of mice deficient for NFAT proteins suggested different roles for the NFAT family of transcription factors in the regulation of cell proliferation and apoptosis. NFAT may also regulate several cell cycle and survival factors influencing tumor growth and survival. Here, we demonstrate that two constitutively active forms of NFAT proteins (CA-NFAT1 and CA-NFAT2 short isoform) induce distinct phenotypes in NIH 3T3 cells. Whereas CA-NFAT1 expression induces cell cycle arrest and apoptosis in NIH 3T3 fibroblasts, CA-NFAT2 short isoform leads to increased proliferation capacity and induction of cell transformation. Furthermore, NFAT1-deficient mice showed an increased propensity for chemical carcinogen-induced tumor formation, and CA-NFAT1 expression subverted the transformation of NIH 3T3 cells induced by the H-rasV12 oncogene. The differential roles for NFAT1 are at least partially due to the protein C-terminal domain. These results suggest that the NFAT1 gene acts as a tumor suppressor gene and the NFAT2 short isoform acts gene as an oncogene, supporting different roles for the two transcription factors in tumor development.