Prednisolone-induced differential gene expression in mouse liver carrying wild type or a dimerization-defective glucocorticoid receptor.
BACKGROUND
Glucocorticoids (GCs) control expression of a large number of genes via binding to the GC receptor (GR). Transcription may be regulated either by binding of the GR dimer to DNA regulatory elements or by protein-protein interactions of GR monomers with other transcription factors. Although the type of regulation for a number of individual target genes is known, the relative contribution of both mechanisms to the regulation of the entire transcriptional program remains elusive. To study the importance of GR dimerization in the regulation of gene expression, we performed gene expression profiling of livers of prednisolone-treated wild type (WT) and mice that have lost the ability to form GR dimers (GRdim).


RESULTS
The GR target genes identified in WT mice were predominantly related to glucose metabolism, the cell cycle, apoptosis and inflammation. In GRdim mice, the level of prednisolone-induced gene expression was significantly reduced compared to WT, but not completely absent. Interestingly, for a set of genes, involved in cell cycle and apoptosis processes and strongly related to Foxo3a and p53, induction by prednisolone was completely abolished in GRdim mice. In contrast, glucose metabolism-related genes were still modestly upregulated in GRdim mice upon prednisolone treatment. Finally, we identified several novel GC-inducible genes from which Fam107a, a putative histone acetyltransferase complex interacting protein, was most strongly dependent on GR dimerization.


CONCLUSIONS
This study on prednisolone-induced effects in livers of WT and GRdim mice identified a number of interesting candidate genes and pathways regulated by GR dimers and sheds new light onto the complex transcriptional regulation of liver function by GCs.
Computational Drug Discovery (CDD), Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University Nijmegen Medical Centre, Geert Grooteplein Zuid 26-28, Nijmegen, the Netherlands.
Raoul
R
Frijters
Wilco
W
Fleuren
Erik J M
EJ
Toonen
Jan P
JP
Tuckermann
Holger M
HM
Reichardt
Hans
H
van der Maaden
Andrea
A
van Elsas
Marie-Jose
MJ
van Lierop
Wim
W
Dokter
Jacob
J
de Vlieg
Wynand
W
Alkema
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D023281:Genomics; D005943:Gluconeogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D011239:Prednisolone / Q000494:pharmacology*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D011965:Receptors, Glucocorticoid / Q000737:chemistry* / Q000378:metabolism*
D051858:Forkhead Transcription Factors; D011965:Receptors, Glucocorticoid; D011239:Prednisolone