Regulation of major histocompatibility complex class I gene expression in thyroid cells. Role of the cAMP response element-like sequence

  • Saji M
  • Shong M
  • Napolitano G
 et al. 
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Abstract

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.

Author-supplied keywords

  • *Gene Expression Regulation
  • Animals
  • Base Sequence
  • Cattle
  • Cyclic AMP Response Element-Binding Protein/geneti
  • Cyclic AMP/pharmacology
  • DNA/metabolism
  • Forskolin/pharmacology
  • Genes, MHC Class I/*genetics
  • Macromolecular Substances
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Receptors, Thyrotropin/genetics
  • Sequence Analysis, DNA
  • Thyroid Gland/*metabolism
  • Thyrotropin/pharmacology

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Authors

  • M Saji

  • M Shong

  • G Napolitano

  • L A Palmer

  • S I Taniguchi

  • M Ohmori

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