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。虽然诸如TNF和干扰素之类的药剂是很好的， 除了已知的I类转录诱导物外，许多其他因素也影响 表情我们已经证明，促甲状腺激素（TSH） 特异性降低甲状腺细胞中I类基因的转录;这 下调是cAMP介导的。三种DNA元素已经被证明 成为cAMP作用的靶点其中之一是一个复杂的元素， 含有经典的CRE，并作为组成型沉默剂发挥作用。 通过CRE的调节是通过组合相互作用实现的 组织特异性和一般性转录因子， 与CRE重叠的序列，5'和3'。 组织特异性 因子TTF 1在不存在cAMP的情况下部分结合该元件 对付消音器的活动cAMP、TTF 1活性 降低，导致增强的沉默剂活性 通过TSEP-1的结合，TSEP-1是一种Y盒结合蛋白， 我是抄写员。组织特异性因子TTF 1和Pax 8也 调节甲状腺球蛋白和TSHR基因的表达， 协调这些基因的调控。第二cAMP响应元件 与之前发现的干扰素反应 元素，IRE。因此，I类IRE作为增强剂响应于 干扰素，但作为对cAMP反应的沉默者。 令人惊讶的是， 干扰素诱导I类启动子活性不仅需要 IRE，还有CRE。因此，cAMP和干扰素都起作用， 通过共同的元素来达到相反的效果。 第三个cAMP反应元件已经在基底膜上被鉴定出来。 启动子 在这种情况下，cAMP的作用靶向于 起始复合物本身，而不是单个DNA序列元件。 这些研究表明，班级的动态调节 基因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性转录因子。此外，本发明还提供了一种方法， 该监管体系提供了一种协调监管机制 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.