DNA Binding of the Glucocorticoid Receptor Is Not Essential for Survival

TLDR

Glucocorticoid receptor transcriptional regulation is essential for survival. The study aimed to determine the relative importance of DNA‑binding‑dependent versus independent GR mechanisms in vivo. A point mutation (A458T) that disrupts GR dimerization and GRE‑dependent transactivation was introduced via Cre/loxP gene targeting to isolate DNA‑binding‑dependent from independent functions. GRdim mutants lacking DNA‑binding activity remain viable, demonstrating that DNA‑binding‑independent GR functions are sufficient for survival.

Abstract

Transcriptional regulation by the glucocorticoid receptor (GR) is essential for survival. Since the GR can influence transcription both through DNA-binding-dependent and -independent mechanisms, we attempted to assess their relative importance in vivo. In order to separate these modes of action, we introduced the point mutation A458T into the GR by gene targeting using the Cre/loxP system. This mutation impairs dimerization and therefore GRE-dependent transactivation while functions that require cross-talk with other transcription factors, such as transrepression of AP-1-driven genes, remain intact. In contrast to GR−/− mice, these mutants termed GRdim are viable, revealing the in vivo relevance of DNA-binding-independent activities of the GR.