RESPONSES OF MHC CLASS I GENES TO EXOGENEOUS STIMULI

MHC I类分子的表达在各种刺激下受到动态调节。虽然诸如TNF和干扰素的试剂是众所周知的I类转录的诱导剂，但许多其他因素也影响表达。我们已经证明，促甲状腺激素（TSH）特异性地降低甲状腺细胞中I类基因的转录，这种下调是cAMP介导的。三种DNA元件已被证明是cAMP作用的靶标。其中之一是一个复杂的元素，包含一个经典的CRE和功能作为一个组成性沉默。通过CRE的调节是通过组织特异性和一般转录因子的组合相互作用实现的，所述转录因子结合与CRE重叠的序列5和3。组织特异性因子TTF 1在没有cAMP的情况下结合该元件，部分抵消沉默物活性。在cAMP之后，TTF 1活性降低，导致沉默物活性增加，其通过TSEP-1（一种降低I类转录的Y盒结合蛋白）的结合而增强。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，建立这些基因的协调调节。第二个cAMP反应元件已被映射到一个30 bp的元件，部分重叠先前确定的干扰素反应元件，IRE。因此，I类IRE作为响应于干扰素的增强剂，但作为响应于cAMP的沉默剂。干扰素诱导I类启动子活性不仅需要IRE，还需要CRE。因此，cAMP和干扰素都通过共同的元件发挥作用，以达到相反的效果。此外，cAMP的作用由PKA介导，PKA诱导CREM家族成员转录因子ICER的表达。ICER是与CRE和IRE DNA序列元件结合的复合物的组分，形成更高级的增强体样结构。第三个cAMP反应元件已被确定在基础启动子。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，I类基因表达的动态调控需要一系列复杂的相互作用，涉及多个调控DNA序列元件，与共同的和组织特异性的转录因子协调相互作用。此外，该调节系统提供了一种协调调节I类基因与组织特异性基因的机制。- 促甲状腺激素，转录，ICER，

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 a 30 bp element that partially overlaps 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. 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. Furthermore, the effects of cAMP are mediated by PKA which induces the expression of the CREM-family member of transcription factors, ICER. ICER is a component of a complex that binds to both the CRE and IRE DNA sequence elements, forming higher-order enhanceosome- like structures. 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. - thyroid stimulating hormone, transcription, ICER,