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Thyroid-hormone-dependent negative regulation of thyrotropin beta gene by thyroid hormone receptors: study with a new

Keiko Nakano1, Akio Matsushita, Shigekazu Sasaki

  • 1Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.

The Biochemical Journal
|November 13, 2003
PubMed

Insights

Thyroid hormone receptor suppresses TSHbeta gene transcription via a mechanism involving its DNA-binding domain. This suppression is mediated by T3-bound receptors and is most potent with the beta2 isoform.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Gene Regulation

Background:

  • The precise molecular mechanisms underlying thyroid hormone receptor's suppression of TSHbeta gene transcription remain unclear.
  • Limited availability of suitable experimental cell lines has hindered research in this area.

Purpose of the Study:

  • To investigate the negative regulation of the TSHbeta gene using a novel assay system.
  • To elucidate the role of thyroid hormone receptor isoforms and their domains in TSHbeta gene suppression.

Main Methods:

  • Development of a reporter gene assay system in non-pituitary CV1 cells using TSHbeta-CAT.
  • Utilizing T3 (3,3',5-tri-iodothyronine) and various thyroid hormone receptor mutants.
  • Analysis of receptor isoform expression in thyrotroph cell lines (TalphaT1).

Main Results:

  • T3-bound thyroid hormone receptor suppressed TSHbeta-CAT reporter activity in a dose-dependent manner.
  • An intact DNA-binding domain of the receptor was essential for TSHbeta gene suppression.
  • The beta2 receptor isoform demonstrated the strongest inhibitory effect and highest expression in TalphaT1 cells.

Conclusions:

  • The DNA-binding domain is critical for thyroid hormone receptor-mediated suppression of TSHbeta gene transcription.
  • While co-activators/co-repressors are not strictly essential, they contribute to the full suppression.
  • The beta2 isoform plays a significant role in regulating TSHbeta gene expression in thyrotrophs.

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