RESPONSES OF MHC CLASS I GENES TO EXOGENEOUS STIMULI

MHC I 类基因对外源刺激的反应

• 批准号: 6289251
• 负责人: DINAH SINGER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289251
• 关键词: DNA binding protein; MHC class I antigen; cyclic AMP; gene expression; genetic enhancer element; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; histocompatibility gene; hormone regulation /control mechanism; immunogenetics; interferons; pharmacogenetics; thyrotropin

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,

MHC-I类分子的表达受多种刺激的动态调节。虽然像肿瘤坏死因子和干扰素这样的药物是众所周知的I类转录的诱导剂，但许多其他因素也会影响表达。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；这种下调是由cAMP介导的。有三种DNA元素已被证明是营地行动的目标。其中之一是一种复杂的元素，它包含一个经典的CRE，并起到结构性消音器的作用。通过Cre的调节是通过组织特异性转录因子和一般转录因子的组合相互作用实现的，这些转录因子与Cre重叠的序列(5和3)结合。组织特异性因子TTF1在没有cAMP的情况下与元件结合，部分抵消沉默活性。在cAMP之后，TTF1活性降低，导致沉默活性增加，而TSEP-1的结合增强了这种活性，TSEP-1是一种Y-box结合蛋白，可以减少I类转录。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，建立这些基因的协调调节。第二个cAMP反应元件已被映射到与先前识别的干扰素反应元件IRE部分重叠的30个碱基的元件。因此，我所提到的这一类对干扰素起到了增强剂的作用，但对cAMP起到了消音器的作用。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素发挥作用，达到相反的效果。此外，cAMP的作用是由PKA介导的，PKA诱导转录因子CREM家族成员ICER的表达。ICER是与Cre和IRE DNA序列元件结合的复合体的一种成分，形成更高阶的增强体样结构。第三个cAMP反应元件已经在基本启动子上被确定。在这种情况下，cAMP的作用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，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，与常见的和组织特异的转录因子协调作用。此外，这个调节系统提供了一种协调调节I类基因和组织特异性基因的机制。-促甲状腺激素、转录、ICER、