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Cited by 49Estrogen and related hormone effectsGenomics and Chromatin DynamicsNF-κB Signaling Pathways

Identification of Endogenous Glucocorticoid Repressed Genes Differentially Regulated by a Glucocorticoid Receptor Mutant Able to Separate between Nuclear Factor-κB and Activator Protein-1 Repression

Bladh, Lars-Göran, Lidén, Johan, Dahlman-Wright, Karin, Reimers, Mark, Nilsson, Stefan, Okret, Sam·2005·Molecular Pharmacology
DOI 10.1124/mol.104.005801
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Abstract

Glucocorticoids are commonly used in the clinic, but long-term treatment is often associated with severe side effects. One way to reduce unwanted effects is to restrict glucocorticoid receptor (GR) signaling through defined pathways. In this study, we examine endogenous target genes regulated by a GR mutant that in contrast to the wild-type GR is unable to repress stimulated nuclear factor-kappaB (NF-kappaB) activity, whereas repression of activator protein-1 (AP-1) activity is maintained. This GR mutant (GRR488Q) harbors a point mutation in the second zinc finger of the DNA binding domain. Its ability to distinguish between NF-kappaB and AP-1 repression is defined using reporter genes regulated by both simple and natural promoters. The inability of GRR488Q to repress NF-kappaB was not related to its inability to activate target genes through a glucocorticoid response element. Furthermore, the discriminating property was observed in three different cell lines, suggesting that this is not a cell-specific effect. These results show that different receptor surfaces or mechanisms are involved in repression of NF-kappaB and AP-1, respectively. It is interesting that the GRR488Q still interacted physically with NF-kappaB. Gene expression profiling of human embryonic kidney 293 cells, which express the wild-type GR and the GRR488Q mutant allowed identification of endogenous genes preferentially repressed by GR interference with NF-kappaB activity. The genes differentially regulated by GRR488Q mutant versus the wild-type GR after 2 h of treatment seem mainly to be involved in control of transcription and cell growth. At 8 h, no such distinction could be seen.

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  • Different GR domains are responsible for NF-κB and AP-1 interactions.

    “This role may not be the same as that for NF-κB because different GR domains are responsible for NF-κB and AP-1 interactions (Bladh et al., 2005).”

    From The Stressed CNS: When Glucocorticoids Aggravate Inflammation (2009) · cites this paper as Bladh et al., 2005

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Authors
Bladh, L.-G., Lidén, J., Dahlman-Wright, K., Reimers, M., Nilsson, S., & Okret, S.
Affiliations
  • Karolinska University Hospital (SE)
  • Karolinska Institutet (SE)
  • National Institutes of Health (US)
  • Karo Pharma (Sweden) (SE)
ORCID
Okret, Sam
Venue
Molecular Pharmacology
Publisher
Elsevier BV
Published
2005-03
Volume
67
Issue
3
Pages
815-826
ISSN
0026-895X (ISSN-L)
DOI
10.1124/mol.104.005801
OpenAlex
W2036130822
Cited by
49
References
41
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 2 · 2013: 5
FWCI
2.13
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Molecular Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
Keywords
glucocorticoid receptor, zinc finger mutations, glucocorticoid response element, transcriptional repression, gene expression profiling, transcriptional regulation, cell growth regulation
MeSH terms
Animals, Base Sequence, Cell Line, Chlorocebus aethiops, Dexamethasone, Gene Expression Regulation, Glucocorticoids, Humans, Kinetics, Phosphatidylethanolamines, Receptors, Glucocorticoid, NF-kappa B, Zinc Fingers, Point Mutation, Genes, Reporter, DNA Primers, Transcription Factor AP-1, Oligonucleotide Array Sequence Analysis

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