Regulation of Major Histocompatibility Complex Class I Gene Expression in Thyroid Cells: ROLE OF THE cAMP RESPONSE ELEMENT-LIKE SEQUENCE

The major histocompatibility complex (MHC) class I gene cAMP response element (CRE)-like site, −107 to −100 base pairs, is a critical component of a previously unrecognized silencer, −127 to −90 bp, important for thyrotropin (TSH)/cAMP-mediated repression in thyrocytes. TSH/cAMP induced-silencer activity is associated with the formation of novel complexes with the 38-base pair silencer, whose appearance requires the CRE and involves ubiquitous and thyroid-specific proteins as follows: the CRE-binding protein, a Y-box protein termed thyrotropin receptor (TSHR) suppressor element protein-1 (TSEP-1); thyroid transcription factor-1 (TTF-1); and Pax-8. TTF-1 is an enhancer of class I promoter activity; Pax-8 and TSEP-1 are suppressors. TSH/cAMP decreases TTF-1 complex formation with the silencer, thereby decreasing maximal class I expression; TSH/cAMP enhance TSEP-1 and Pax-8 complex formation in association with their repressive actions. Oligonucleotides that bind TSEP-1, not Pax-8, prevent formation of the TSH/cAMP-induced complexes associated with TSH-induced class I suppression, TSEP-1 appears to be the dominant repressor factor associated with TSH/cAMP-decreased class I activity and formation of the novel complexes. TSEP-1, TTF-1, and/or Pax-8 are involved in TSH/cAMP-induced negative regulation of the TSH receptor gene in thyrocytes, suppression of MHC class II, and up-regulation of thyroglobulin. TSH/cAMP coordinate regulation of common transcription factors may, therefore, be the basis for self-tolerance and the absence of autoimmunity in the face of TSHR-mediated increases in gene products that are important for thyroid growth and function but are able to act as autoantigens.

主要组织相容性复合体（MHC）I类基因的环腺苷酸反应元件（CRE）样位点，即 -107至 -100碱基对，是一个先前未被识别的沉默子（ -127至 -90bp）的关键组成部分，对甲状腺细胞中促甲状腺素（TSH）/环腺苷酸介导的抑制作用非常重要。TSH/环腺苷酸诱导的沉默子活性与38碱基对沉默子形成新的复合物有关，其出现需要CRE，并涉及以下普遍存在的和甲状腺特异性的蛋白质：CRE结合蛋白、一种称为促甲状腺素受体（TSHR）抑制元件蛋白 -1（TSEP -1）的Y盒蛋白、甲状腺转录因子 -1（TTF -1）以及Pax -8。TTF -1是I类启动子活性的增强子；Pax -8和TSEP -1是抑制子。TSH/环腺苷酸减少TTF -1与沉默子形成复合物，从而降低I类基因的最大表达量；TSH/环腺苷酸增强TSEP -1和Pax -8复合物的形成，这与其抑制作用相关。结合TSEP -1而非Pax -8的寡核苷酸可阻止与TSH诱导的I类基因抑制相关的TSH/环腺苷酸诱导复合物的形成。TSEP -1似乎是与TSH/环腺苷酸降低I类基因活性以及新复合物形成相关的主要抑制因子。TSEP -1、TTF -1和/或Pax -8参与甲状腺细胞中TSH/环腺苷酸对TSH受体基因的负调控、MHC II类基因的抑制以及甲状腺球蛋白的上调。因此，TSH/环腺苷酸对共同转录因子的协同调控可能是在面对对甲状腺生长和功能重要但可作为自身抗原的TSHR介导的基因产物增加时自身耐受和自身免疫缺失的基础。