Statin-induced blockade of prenylation alters nucleocytoplasmic shuttling of GTP-binding proteins γ2 and β2 and enhances their suppressive effect on glucocorticoid receptor transcriptional activity

Tomoshige Kino, T. Kozasa, G. P. Chrousos

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: We previously reported that the guanine tri-phosphate-binding proteins (G) β and γ are both localized in the nucleus, in addition to their expected cytoplasmic/plasma membrane localization. These proteins, as a heterodimeric complex, suppress glucocorticoid response element-mediated transcriptional activity of the glucocorticoid receptor through direct physical interactions between Gβ and the glucocorticoid receptor. Materials and methods: As Gγ is prenylated at a cysteine residue in its C-terminal portion, and as this post-translational modification is required for many of the known Gβ/Gγ activities, we examined the effect of its absence or diminution on Gβ/Gγ-induced suppression of glucocorticoid receptor-induced transcriptional activity. Results: In a functional reporter assay, Gγ2C68S, which is defective at the prenylation site, was more potent than the wild-type Gγ2 at increasing Gβ2-induced suppression of glucocorticoid receptor transactivation. Interestingly, the enhanced green fluorescent protein fusion of this mutant Gγ2 was localized preferentially in the nucleus, while it was absent from the plasma membrane. Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that abrogates the prenylation of Gγ, shifted the subcellular localization of enhanced green fluorescence protein-fused Gγ2 and Gβ2 from the cytoplasm/plasma membrane to the nucleus and further suppressed glucocorticoid receptor-induced transcriptional activity. Conclusions: These findings indicate that not only is the natural covalent addition of the prenyl residue to Gγ unnecessary for the transcriptional suppression induced by Gβ/Gγ on the glucocorticoid receptor, but rather helps retain the Gβ/Gγ complex away from the nucleus decreasing its antiglucocorticoid actions.

Original languageEnglish
Pages (from-to)508-513
Number of pages6
JournalEuropean Journal of Clinical Investigation
Volume35
Issue number8
DOIs
Publication statusPublished - Aug 2005
Externally publishedYes

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Keywords

  • Glucocorticoid receptor
  • GTP-binding protein β
  • GTP-binding protein γ
  • Prenylation
  • Statins
  • Subcellular localization

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry
  • Clinical Biochemistry

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