REGULATION OF MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I GENE-EXPRESSION IN THYROID-CELLS - ROLE OF THE CAMP RESPONSE ELEMENT-LIKE SEQUENCE

The major histocompatibility complex (MBC) class I gene cAMP response element (CBE)-like site, -107 to - 100 base pairs, is a critical compo nent 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 c omplexes 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 f actor-1 (TTF-1); and Pax-8. TTF-1 is as enhancer of Glass I promoter a ctivity; Pax-8 and TSEP-1 are suppressors, TSH/cAMP decreases TTF-1 co mplex formation with the silencer, thereby decreasing maximal class I expression; TSH/cAMP enhance TSEP-1 and Pax-8 complex formation in ass ociation with their repressive actions, Oligonucleotides that bind TSE P-1, not Pax-8, prevent formation of the TSH/cAMP-induced complexes as sociated with TSH-induced class I suppression, i.e. TSEP-1 appears to be the dominant repressor factor associated with TSH/cAMP-decreased cl ass I activity and formation of the novel complexes. TSEP-1, TTF-1, an d/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 fop self-tolerance and the absence of autoimmunity iu. the face of TSHR-mediated increase s in gene products that are important for thyroid growth and function but are able to act as autoantigens.