THE FAMILY OF KB REGULATORS FOR GENES IN THE IMMUNE RESPONSE

几种淋巴因子和其他分子的基因调控 参与免疫应答的DNA依赖于称为kB的10 bp DNA序列。 这个序列结合了一个不断增长的核蛋白家族，其中有几个 与rel癌基因有关，能够严格控制 这些基因的转录。 重要的是，kB序列存在于 人类免疫缺陷病毒（HIV）。 kB的一个主要特征是 它允许以高度调节的方式转录 在时间上和在特定基因的适当细胞类型中。 我们 试图阐明这种特殊的调节是如何发生的。 我们有 发现IL-2受体α链基因增强子特异性作用于T细胞， 细胞通过NF-kB和另一种基因调节蛋白的合作 称为SRF。 我们还发现kB之间DNA序列的微观异质性 网站具有监管意义。 通过研究正态非变换T 在淋巴细胞克隆中，我们发现了一种新的核复合物，称为NF-kC （以前称为NF-CYT 1），优先与kB位点相互作用 在白细胞介素2基因中。 NF-kC在许多不同的细胞中的存在， 生物学条件与IL-2基因表达呈负相关， T细胞。 这表明它可能是一种负调节剂。 我们已经表明 NF-kC由NF-kB p50亚基的同源二聚体复合物组成， 它可以直接抑制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 假设它可能在抑制HIV病毒转录中起作用， 静息T细胞 重要的是，我们已经发现， NF-kC复合物由抑制蛋白（IkC）控制， 在抗原刺激后将NF-kC复合物隔离在细胞核中。 目前正在努力从分子水平克隆IkC分子。

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.