Growth hormone regulates deiodinase type 2 and 3 expression via GATA

Abstract

Objective

Growth hormone (GH) is involved in bone and skeletal muscle growth directly or indirectly via STAT5 and/or insulin-like growth factor (IGF)-1. Thyroid hormone (TH) is essential for general cellular growth and metabolic regulation. While both GH and TH are essential for growth, their actions may partially complement each other in conditions of hormonal deficiency. For example, TH can enhance GH secretion and sensitivity, while GH is ineffective in Refetoff syndrome due to TH receptor dysfunction. However, the underlying molecular mechanism remains unclear. In this study, we investigated the molecular mechanisms underlying the complementarity between GH and TH, paying special attention to the effects of GH on the expression of both iodothyronine deiodinase (DIO) type 2 (DIO2) and type 3 (DIO3).

Design

The effects of growth hormone (GH) on DIOs were examined using reporter assays, chromatin immunoprecipitation, quantitative PCR, and western blotting using HEK293-derived TSA201 cells and mouse ATDC5 chondrocytes.

Results

GH induced the mRNA and protein expression of DIOs in ATDC5 cells via STAT5/GATA. GATAs activate the promoter activity of both DIOs. The binding sites for GATA on the DIO promoter were located −87 bp and − 75 bp upstream from the TSS for the DIO2 promoter and − 6 bp upstream from the TSS for the DIO3 promoter, respectively. GH-induced expression of DIOs in ATDC5 cells was abolished by K-7174, a GATA-specific inhibitor.

Conclusion

The present study demonstrates that GH regulates DIO2 and DIO3 expression via JAK/STAT5/GATAs after binding to GHR. This is the first report on the molecular mechanisms underlying GH-dependent compensation of TH action. (256 words).