Responses of MHC Class I Genes to Exogeneous Stimuli

MHC I类的表达受到多种刺激的动态调节。诸如TNF和干扰素之类的药物是众所周知的I类转录诱导剂。相反，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。先前的实验室研究主要集中在tsh介导的抑制机制上，而最近的研究正在通过转录共激活剂CIITA研究干扰素介导的诱导的分子基础。CIITA共激活因子对MHC II类基因的转录激活至关重要，并介导MHC I类转录的增强。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的CRE，位于-100和-107 bp之间，但进一步增强了一系列上游序列元素。有趣的是，CIITA介导的激活所需的DNA序列不同于构成型转录。此外，CIITA激活所需的转录因子也不同于构成型转录：构成型转录需要TAFII250，而CIITA激活则不需要。特别有趣的是，我们发现CIITA含有一个内在的乙酰转移酶（AT）活性，该活性映射到CIITA n端段的一个区域，位于氨基酸36和132之间。这种AT活性受c端gtp结合域的调控。ciita介导的交易依赖于AT活性。

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.