THE FAMILY OF KAPPA B 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依赖于一个10 bp的DNA序列， 卡帕 这个序列结合了一个不断增长的核蛋白家族， 与rel癌基因相关， 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。 的一个主要特征 kappaB序列是，它允许转录在一个高度调节的 在时间上和特定基因的适当细胞类型中形成。 我们试图阐明这种特殊的调节是如何发生的。 在 研究非转化T细胞中NF-κ B的分子活化 在抗原和抗原呈递细胞（APC）刺激后， 发现单独暴露于APC有时就足够了。 NF-kappaB 单独APC的诱导似乎是由于TNF α的分泌。 这些 因此，结果建立了抗原受体非依赖性途径， 在T细胞活化期间调节NF-κ B。 我们还发现， 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物， 称为NF-kappaC（以前称为NF-CYT 1）， 在白细胞介素2基因上有一个kappaB位点。 NF-κ C的存在 在许多不同的生物条件下， IL-2基因在T细胞中的表达。 这表明它可能是一个消极的 调节器 我们已经证明NF-κ C由同源二聚体复合物组成， NF-κ B p50亚基的表达，并且它可以直接抑制NF-κ B p50亚基的功能。 IL-2启动子。 非常重要的是，该因子与 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 NF-κ C复合物的结合活性受一种 抑制性蛋白（IkappaC），其将NF-κ C复合物隔离在 抗原刺激后的细胞核。 目前的证据表明， p50复合物的抑制剂可以是原癌基因bcl-3，即 在特定类型的染色体易位的断点处发现， 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.