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, i.e. 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.
Saji
M
M
Cell Regulation Section, Metabolic Diseases Branch, NIDDKD, National Institutes of Health, Bethesda, Maryland 20892, USA.
Shong
M
M
Napolitano
G
G
Palmer
L A
LA
Taniguchi
S I
SI
Ohmori
M
M
Ohta
M
M
Suzuki
K
K
Kirshner
S L
SL
Giuliani
C
C
Singer
D S
DS
Kohn
L D
LD
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D005805:Genes, MHC Class I / Q000235:genetics*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D011989:Receptors, Thyrotropin / Q000235:genetics; D017422:Sequence Analysis, DNA; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000494:pharmacology
D017362:Cyclic AMP Response Element-Binding Protein; D046911:Macromolecular Substances; D011989:Receptors, Thyrotropin; D005576:Colforsin; D013972:Thyrotropin; D004247:DNA; D000242:Cyclic AMP