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: 6559059
• 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/6559059
• 关键词: MHC class I antigen; acyltransferase; enzyme activity; gene expression; genetic promoter element; genetic transcription; interferons; transcription factor

Expression of MHC class I is dynamically regulated in response to a variety of stimuli. Agents such as TNF and interferon are well known inducers of class I transcription. In contrast, thyroid stimulating hormone (TSH) specifically reduces class I gene transcription in thyrocytes; this down-regulation is cAMP-mediated. Whereas previous studies in the laboratory have focused on the mechanisms of TSH-mediated repression, recent studies are examining the molecular basis of interferon-mediated induction through the transcriptional co-activator CIITA. The CIITA co-activator is essential for transcriptional activation of MHC class II genes and mediates enhanced MHC class I transcription. Class I promoter activation by CIITA requires both the downstream core promoter and upstream sequences. Activation is absolutely dependent on the upstream CRE, located between -100 and -107 bp, but is further enhanced by a series of upstream sequence elements. Interestingly, the DNA sequence requirements for CIITA mediated activation are distinct from those of constitutive transcription. Furthermore, the transcription factor requirements for CIITA activation are also distinct from those of constitutive transcription: constitutive transcription requires TAFII250 whereas CIITA activation does not. Of particular interest, we have found that CIITA contains an intrinsic acetyl transferase (AT) activity that maps to a region within the N-terminal segment of CIITA, between amino acids 36 and 132. This AT activity is regulated by the C-terminal GTP-binding domain. CIITA-mediated transactivation depends on the AT activity.

MHC-I类分子的表达受多种刺激的动态调节。众所周知，肿瘤坏死因子和干扰素是I类转录的诱导剂。相反，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。实验室以前的研究主要集中在TSH介导的抑制机制上，而最近的研究正在研究干扰素通过转录共激活因子CIITA介导的诱导的分子基础。CIITA共激活子对于MHC-II类基因的转录激活是必不可少的，并介导增强的MHC-I类转录。CIITA对I类启动子的激活既需要下游核心启动子，也需要上游序列。激活完全依赖于上游的Cre，位于-100到-107bp之间，但一系列上游序列元件进一步增强了激活。有趣的是，CIITA介导的激活对DNA序列的要求与构成转录的不同。此外，CIITA激活对转录因子的要求也与构成转录不同：构成转录需要TAFII250，而CIITA激活不需要。 特别有趣的是，我们发现CIITA含有内在的乙酰转移酶(AT)活性，该活性映射到CIITA的N-末端片段中的36和132个氨基酸之间。这种AT活性受C-末端GTP结合域的调节。CIITA介导的反式激活依赖于AT活性。