THE FAMILY OF KAPPA B 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10个碱基对的DNA序列， 卡帕B。这个序列结合了一个不断增长的核蛋白家族，几个 其中与rel癌基因相关的基因，能够紧密地 控制这些基因的转录。重要的是，kappaB序列 在人类免疫缺陷病毒(HIV)中发现。的一个基本特征 KappaB序列是它允许在高度调控的 在时间上和在适当的细胞类型中为特定的基因设计时尚。 我们正试图阐明这一特定规则是如何发生的。在……里面 未转化T细胞中核因子-kappaB分子活化的研究 在抗原和抗原提呈细胞(APC)的刺激下，我们 发现仅接触APC一项有时就足够了。核因子-kappaB APC的单独诱导似乎是由于分泌了TNFα。这些 结果建立了一条不依赖于抗原受体的UP受体通路。 核因子-kappaB在T细胞活化过程中的调节。 我们还发现DNA序列中的微观异质性在 KappaB位点具有调控意义。通过研究正常的非 转化的T淋巴细胞克隆我们发现了一种新的核复合体， 称为核因子-kappaC(以前称为核因子-细胞周期蛋白1)，优先相互作用 在白介素2基因中有一个kappaB位点。核因子-kappaC的存在 在许多不同的生物条件下是负相关的 T细胞表达IL-2基因。这表明它可能是一个负面的 调整器。我们已经证明了核因子-kappaC是由同源二聚体组成的 核因子-kappaB p50亚基的活性，并可直接抑制其功能 IL-2启动子。非常重要的是，该因素与 HIV的增强子区域。我们推测它可能在抑制 HIV病毒在静息T细胞中的转录。重要的是，我们发现 核因子-kappaC复合体的结合活性受 抑制蛋白(IkappaC)将核因子-kappaC复合体隔离在 抗原刺激后的细胞核。目前有证据表明， P50复合体的抑制物可能是原癌基因bcl3，即 在特定类型的染色体易位的断裂点发现 淋巴瘤。

Regulation of genes for several lymphokines as well as other molecules involved in the immune response depend on a 10 bp DNA sequence termed, kappaB. 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 kappaB sequence is found in the human immunodeficiency virus (HIV). A cardinal feature of the kappaB 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. In studying the molecular activation of NF-kappaB in nontransformed T cells following stimulation by antigen and antigen-presenting cells (APCs), we found that exposure to APCs alone was sometime sufficient. NF-kappaB induction by APC's alone appeared due to the secretion of TNFalpha. These results thus establish an antigen receptor-independent pathway for the up- regulation of NF-kappaB during T cell activation. We have also found that the microheterogeneity in DNA sequence among kappaB sites has regulatory significance. By studying normal non- transformed T lymphocyte clones we discovered a novel nuclear complex, termed NF-kappaC (previously called NF-CYT1) that interacts preferentially with a kappaB site in the interleukin-2 gene. The presence of NF-kappaC 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-kappaC consists of a homodimeric complex of the NF-kappaB 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-kappaC complex is governed by an inhibitory protein (IkappaC) that sequesters the NF-kappaC complex in the nucleus following antigen stimulation. Evidence currently suggests that the inhibitor of the p50 complex may be the proto-oncogene bcl-3, that is found at the breakpoint of chromosomal translocation in specific types of lymphomas.