The transcription factor NFAT5 is required for cyclin expression and cell cycle progression in cells exposed to hypertonic stress.
The transcription factor NFAT5 is required for cyclin expression and cell cycle progression in cells exposed to hypertonic stress.
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DOI：
10.1371/journal.pone.0005245
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Aramburu J
中科院分区：
文献类型：
--
作者：
Drews-Elger K;Ortells MC;Rao A;López-Rodriguez C;Aramburu J
高张力可以扰乱细胞功能，诱导DNA损伤样反应，并抑制增殖。转录因子NFAT5诱导渗透压保护基因产物，使细胞适应持续的高渗条件。虽然已知NFAT5缺陷的淋巴细胞和肾髓质细胞在高渗应激下的增殖能力和活性降低，但对该因子在DNA损伤反应和细胞周期调节中的作用了解较少。我们已经产生了条件基因敲除小鼠来获得NFAT5−/−T淋巴细胞，我们将其作为增殖细胞的模型来研究NFAT5依赖的反应。我们发现，高张力通过诱导p53、p21和GADD45的表达、细胞周期蛋白的下调和细胞周期停滞，触发了早期的、非NFAT5依赖的、遗传毒性应激样反应。在野生型细胞中，NFAT5依赖的适应期诱导了渗透保护基因的表达，下调了应激标志物，恢复了细胞周期蛋白的表达和增殖，并在S和G2/M细胞中显示了增强的NFAT5转录活性。相反，NFAT5−/−细胞不能诱导渗透保护基因，生存能力较差。存活的−/−细胞虽然下调了遗传毒性应激标志物的表达，但其细胞周期停滞在G1/S和G2/M期，这与细胞周期蛋白E1、A2和B1的表达减少有关。我们还表明，在患者和渗透调节紊乱动物模型的血浆中发生的病理性高张水平，抑制了新鲜NFAT5−/−淋巴细胞中T细胞受体刺激反应中细胞周期蛋白和极光B激酶的诱导。我们的结论是，NFAT5通过诱导渗透适应性反应，使细胞表达细胞周期进展所需的基本调节因子，促进了高渗条件下的细胞增殖。
Hypertonicity can perturb cellular functions, induce DNA damage-like responses and inhibit proliferation. The transcription factor NFAT5 induces osmoprotective gene products that allow cells to adapt to sustained hypertonic conditions. Although it is known that NFAT5-deficient lymphocytes and renal medullary cells have reduced proliferative capacity and viability under hypertonic stress, less is understood about the contribution of this factor to DNA damage responses and cell cycle regulation. We have generated conditional knockout mice to obtain NFAT5−/− T lymphocytes, which we used as a model of proliferating cells to study NFAT5-dependent responses. We show that hypertonicity triggered an early, NFAT5-independent, genotoxic stress-like response with induction of p53, p21 and GADD45, downregulation of cyclins, and cell cycle arrest. This was followed by an NFAT5-dependent adaptive phase in wild-type cells, which induced an osmoprotective gene expression program, downregulated stress markers, resumed cyclin expression and proliferation, and displayed enhanced NFAT5 transcriptional activity in S and G2/M. In contrast, NFAT5−/− cells failed to induce osmoprotective genes and exhibited poorer viability. Although surviving NFAT5−/− cells downregulated genotoxic stress markers, they underwent cell cycle arrest in G1/S and G2/M, which was associated with reduced expression of cyclins E1, A2 and B1. We also show that pathologic hypertonicity levels, as occurring in plasma of patients and animal models of osmoregulatory disorders, inhibited the induction of cyclins and aurora B kinase in response to T cell receptor stimulation in fresh NFAT5−/− lymphocytes. We conclude that NFAT5 facilitates cell proliferation under hypertonic conditions by inducing an osmoadaptive response that enables cells to express fundamental regulators needed for cell cycle progression.
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