Trama J, Lu Q, Hawley R G, Ho S N
Department of Pathology, University of California at San Diego, La Jolla, CA 92093, USA.
J Immunol. 2000 Nov 1;165(9):4884-94. doi: 10.4049/jimmunol.165.9.4884.
NFAT DNA binding complexes regulate programs of cellular activation and differentiation by translating receptor-dependent signaling events into specific transcriptional responses. NFAT proteins, originally defined as calcium/calcineurin-dependent regulators of cytokine gene transcription in T lymphocytes, are expressed in many different cell types and represent critical signaling intermediates that mediate an increasingly wide spectrum of biologic responses. Recent studies have identified a novel protein containing a region of similarity to the NFAT DNA binding domain. Here we demonstrate that this protein, designated NFATL1 (also known as tonicity enhancer binding protein and NFAT5) is expressed at high levels in the thymus but is undetectable in mature lymphocytes. However, NFATL1 can be induced in both primary quiescent T lymphocytes and differentiated Th1 and Th2 cell populations upon mitogen- or Ag receptor-dependent activation. The induction of NFATL1 protein, as well as NFATL1-dependent transcription, is inhibited by cyclosporin A and FK506, and expression of constitutively active calcineurin induces NFATL1-dependent transcription. Overexpression of NFATc1 and inhibition of NFATc activity through the use of a dominant negative NFATc1 protein have no affect on NFATL1-dependent transcription, indicating that NFATc proteins do not play a role in the calcineurin-dependent induction of NFATL1. Interestingly, induction of NFATL1 by a hyperosmotic stimulus is not blocked by the inhibition of calcineurin. Moreover, osmotic stress response genes such as aldose reductase are not induced upon T cell activation. Thus inducible expression of NFATL1 represents a mechanism by which receptor-dependent signals as well as osmotic stress signals are translated into transcriptional responses that regulate cell function.
NFAT DNA结合复合物通过将受体依赖性信号事件转化为特定的转录反应来调节细胞激活和分化程序。NFAT蛋白最初被定义为T淋巴细胞中细胞因子基因转录的钙/钙调神经磷酸酶依赖性调节因子，在许多不同的细胞类型中表达，是介导越来越广泛的生物学反应的关键信号中间体。最近的研究发现了一种新的蛋白质，其含有与NFAT DNA结合结构域相似的区域。在此我们证明，这种名为NFATL1（也称为张力增强子结合蛋白和NFAT5）的蛋白质在胸腺中高水平表达，但在成熟淋巴细胞中检测不到。然而，在有丝分裂原或抗原受体依赖性激活后，原代静止T淋巴细胞以及分化的Th1和Th2细胞群体中均可诱导NFATL1。环孢菌素A和FK506可抑制NFATL1蛋白的诱导以及NFATL1依赖性转录，而组成型活性钙调神经磷酸酶的表达可诱导NFATL1依赖性转录。NFATc1的过表达以及通过使用显性负性NFATc1蛋白抑制NFATc活性对NFATL1依赖性转录没有影响，这表明NFATc蛋白在钙调神经磷酸酶依赖性诱导NFATL1中不起作用。有趣的是，高渗刺激诱导NFATL1不受钙调神经磷酸酶抑制的阻断。此外，T细胞激活后不会诱导醛糖还原酶等渗透应激反应基因。因此，NFATL1的可诱导表达代表了一种机制，通过该机制受体依赖性信号以及渗透应激信号被转化为调节细胞功能的转录反应。
