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首页> 外文期刊>Molecular and Cellular Biology >NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains
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NFAT2 Isoforms Differentially Regulate Gene Expression, Cell Death, and Transformation through Alternative N-Terminal Domains

机译：NFAT2亚型差异调节基因表达，细胞死亡，并通过替代的N端域转换。

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The NFAT (nuclear factor of activated T cells) family of transcription factors is composed of four calcium-responsive proteins (NFAT1 to -4). The NFAT2 (also called NFATc1) gene encodes the isoforms NFAT2α and NFAT2β that result mainly from alternative initiation exons that provide two different N-terminal transactivation domains. However, the specific roles of the NFAT2 isoforms in cell physiology remain unclear. Because previous studies have shown oncogenic potential for NFAT2, this study emphasized the role of the NFAT2 isoforms in cell transformation. Here, we show that a constitutively active form of NFAT2α (CA-NFAT2α) and CA-NFAT2β distinctly control death and transformation in NIH 3T3 cells. While CA-NFAT2α strongly induces cell transformation, CA-NFAT2β leads to reduced cell proliferation and intense cell death through the upregulation of tumor necrosis factor alpha (TNF-α). CA-NFAT2β also increases cell death and upregulates Fas ligand (FasL) and TNF-α in CD4+ T cells. Furthermore, we demonstrate that differential roles of NFAT2 isoforms in NIH 3T3 cells depend on the N-terminal domain, where the NFAT2β-specific N-terminal acidic motif is necessary to induce cell death. Interestingly, the NFAT2α isoform is upregulated in Burkitt lymphomas, suggesting an isoform-specific involvement of NFAT2 in cancer development. Finally, our data suggest that alternative N-terminal domains of NFAT2 could provide differential mechanisms for the control of cellular functions.
机译：转录因子的NFAT（活化T细胞的核因子）家族由四个钙响应蛋白（NFAT1至-4）组成。 NFAT2（也称为NFATc1）基因编码同工型NFAT2α和NFAT2β，其主要来自提供两个不同N末端反式激活域的替代起始外显子。但是，尚不清楚NFAT2亚型在细胞生理中的具体作用。因为以前的研究显示了NFAT2的致癌潜力，所以本研究强调了NFAT2亚型在细胞转化中的作用。在这里，我们显示NFAT2α（CA-NFAT2α）和CA-NFAT2β的组成型活性形式明显控制NIH 3T3细胞的死亡和转化。虽然CA-NFAT2α强烈诱导细胞转化，但CA-NFAT2β通过上调肿瘤坏死因子α（TNF-α）导致细胞增殖减少和强烈的细胞死亡。 CA-NFAT2β还可以增加细胞死亡，并上调CD4 + T细胞中的FasL和FasL。此外，我们证明NFAT2亚型在NIH 3T3细胞中的不同作用取决于N末端域，其中NFAT2β特异性N末端酸性基序是诱导细胞死亡所必需的。有趣的是，伯基特淋巴瘤中的NFAT2α亚型上调，表明NFAT2的一种亚型特异性参与了癌症的发展。最后，我们的数据表明，NFAT2的替代性N末端域可以为控制细胞功能提供不同的机制。

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