RESPONSES OF MHC CLASS I GENES TO EXOGENOUS STIMULI

MHC I类分子的表达是动态调节的 各种刺激。而像肿瘤坏死因子和干扰素这样的药物很好 已知的I类转录诱导物，许多其他因素也影响 表情。我们已经证明促甲状腺激素(TSH) 特异性地减少甲状腺细胞中I类基因的转录；这 下调调控是由cAMP介导的。已经显示了三种DNA元素 成为营地行动的目标。其中之一是一个复杂的元素， 包含一种经典的CRE，并起到结构性消声器的作用。 通过CRE的监管是通过组合互动实现的 组织特异的和一般的转录因子，结合到 与Cre重叠的序列，包括5‘和3’。组织特异性 在没有cAMP的情况下，因子TTF1部分地结合该元件 对抗消音器的活动。夏令营结束后，TTF1活动 减少，导致消音器活性增加，从而增强 通过TSEP-1的结合，一种Y-box结合蛋白降低类 我抄写的。组织特异性因子TTF1和Pax 8也 调节甲状腺球蛋白和TSHR基因的表达，建立 协调这些基因的调节。第二个阵营反应因素 已经被映射到先前发现的干扰素反应 元素，愤怒。因此，我所关心的类充当了响应的增强器 干扰素，但作为对cAMP反应的消音器。令人惊讶的是， 干扰素诱导I类启动子活性不仅需要 愤怒，但也包括CRE。因此，cAMP和干扰素都有作用 通过共同的元素达到相反的效果。 第三个cAMP反应元件已在基底部被确定 推动者。在这种情况下，cAMP的效果针对的是 起始复合体本身，而不是单个DNA序列元件。 这些研究表明，班级的动态调节 I基因的表达需要一系列复杂的相互作用 多个调控DNA序列元件，协调相互作用 与常见的和组织特异的转录因子结合。此外, 这一监管体系提供了一种协调监管的机制 具有组织特异性基因的I类基因。

Expression of MHC class I is dynamically regulated in response to a variety of stimuli. While agents such as TNF and interferon are well known inducers of class I transcription, many other factors also affect expression. We have shown that thyroid stimulating hormone (TSH) specifically reduces class I gene transcription in thyrocytes; this down-regulation is cAMP-mediated. Three DNA elements have been shown to be targets of cAMP action. One of these is a complex element that contains a classical CRE and functions as a constitutive silencer. Regulation through the CRE is achieved by combinatorial interactions of tissue specific and general transcription factors, that bind to sequences overlapping the CRE, both 5' and 3'. The tissue specific factor, TTF1, binds the element in the absence of cAMP, partially countering the silencer activity. Following cAMP, TTF1 activity decreases, resulting in increased silencer activity that is potentiated by the binding of TSEP-1, a Y-box binding protein that reduces class I transcription. The tissue specific factors, TTF1 and Pax 8, also regulate expression of thyroglobulin and the TSHR genes, establishing coordinate regulation of these genes. A second cAMP-response element has been mapped to the previously identified interferon response element, IRE. Thus, the class I IRE acts as an enhancer in response to interferon, but as a silencer in response to cAMP. Surprisingly, induction of class I promoter activity by interferon requires not only the IRE, but also the CRE. Thus, both cAMP and interferon function through common elements to achieve opposite effects. The third cAMP-responsive element has been identified at the basal promoter. In this case, the effect of cAMP is targetted to the initiation complex itself, and not to a single DNA sequence element. These studies have demonstrated that the dynamice regulation of class I gene expression requires a series of complex interactions involving multiple regulatory DNA sequence elements, coordinately interacting with common and tissue specific transcription factors. In addition, this regulatory system provides a mechanism for coordinate regulation of class I genes with tissue specific genes.