THE FAMILY OF KB REGULATORS FOR GENES IN THE IMMUNE RESPONSE

几种淋巴因子及其他分子的基因调控 参与免疫反应依赖于一个称为kB的10个碱基的DNA序列。 这个序列结合了一个不断增长的核蛋白家族，其中几个 与rel癌基因有关，它们能够紧密地控制 这些基因的转录。重要的是，kB序列在 人类免疫缺陷病毒(HIV)。知识经济的一个基本特征 序列是它允许以高度调控的方式转录 在时间上和在特定基因的适当细胞类型中。我们是 试图阐明这一特定规则是如何发生的。我们有 发现IL-2受体α链基因增强子在T细胞中起特异性作用 核因子-kB与另一基因调控蛋白协同作用的细胞 称为SRF。 我们还发现，kB间DNA序列的微观异质性 网站具有监管意义。通过研究正常的非变换T细胞 淋巴细胞克隆我们发现了一种新的核复合体，称为核因子-KC (以前称为NF-CyT1)，优先与kB站点相互作用 在白介素2基因中。核因子-KC在许多不同组织中的存在 肿瘤生物学条件与IL-2基因表达呈负相关 T细胞。这表明，它可能是一个负面监管机构。我们已经展示了 该核因子-KC由核因子-kB p50亚基的同源二聚体复合体和 可以直接抑制IL-2启动子的功能。非常 值得注意的是，该因子与HIV的增强子区域结合。我们 推测它可能在抑制HIV病毒转录方面发挥作用 静息T细胞。重要的是，我们发现它的结合活性 核因子-KC复合体由一种抑制蛋白(IKC)控制，该蛋白 在抗原刺激后，将核因子-KC复合体隔离在细胞核内。 目前正在努力对IKC分子进行分子克隆。

Regulation of genes for several lymphokines as well as other molecules involved in the immune response depend on a 10 bp DNA sequence termed, kB. This sequence binds a growing family of nuclear proteins, several of which are related to the rel oncogene, that are capable of tightly governing transcription of these genes. Importantly, the kB sequence is found in the human immunodeficiency virus (HIV). A cardinal feature of the kB sequence is that it permits transcription in a highly regulated fashion both temporally and in appropriate cell-types for specific genes. We are attempting to elucidate how this specific regulation occurs. We have found the IL-2 receptor alpha chain gene enhancer acts specifically in T cells through cooperation of NF-kB and another gene regulatory protein called SRF. We have also found that the microheterogeneity in DNA sequence among kB sites has regulatory significance. By studying normal non-transformed T lymphocyte clones we discovered a novel nuclear complex, termed NF-kC (previously called NF-CYT1) that interacts preferentially with a kB site in the interleukin-2 gene. The presence of NF-kC in a number of different biological conditions is inversely correlated with IL-2 gene expression in T cells. This suggests it may be a negative regulator. We have shown that NF-kC consists of a homodimeric complex of the NF-kB p50 subunit and that it can directly repress the function of the IL-2 promoter. Very significantly, this factor binds to the enhancer region of HIV. We postulate it may have a role in suppressing HIV viral transcription in resting T cells. Importantly, we have found that the binding activity of the NF-kC complex is governed by an inhibitory protein (IkC) that sequesters the NF-kC complex in the nucleus following antigen stimulation. Efforts are underway to molecularly clone the IkC molecule.