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: 6433153
• 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/6433153
• 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. 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类分子的表达在各种刺激下受到动态调节。诸如TNF和干扰素的试剂是熟知的I类转录诱导剂。相反，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;这种下调是cAMP介导的。而以前的研究在实验室中集中在TSH介导的抑制机制，最近的研究正在检查干扰素介导的诱导通过转录辅激活因子CIITA的分子基础。 CIITA共激活因子对于MHC II类基因的转录激活是必需的，并且介导增强的MHC I类转录。CIITA激活I类启动子需要下游核心启动子和上游序列。 激活完全依赖于上游CRE，位于-100和-107 bp之间，但通过一系列上游序列元件进一步增强。有趣的是，CIITA介导的激活的DNA序列要求与组成型转录的DNA序列要求不同。此外，CIITA激活的转录因子要求也不同于组成型转录：组成型转录需要TAFII 250，而CIITA激活不需要。特别令人感兴趣的是，我们发现CIITA含有内在的乙酰转移酶（AT）活性，其映射到CIITA的N-末端片段内的氨基酸36和132之间的区域。这种AT活性由C-末端GTP结合结构域调节。 CIITA介导的反式激活依赖于AT活性。