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TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile

Karen Dendoncker (UGent) , Steven Timmermans (UGent) , Jolien Vandewalle (UGent) , Melanie Eggermont (UGent) , Joanna Lempiäinen, Ville Paakinaho, Evelien Van Hamme (UGent) , Sylviane Dewaele (UGent) , Sofie Vandevyver (UGent) , Marlies Ballegeer (UGent) , et al.
(2019) PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 116(26). p.12942-12951
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Abstract
Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the therapeutic effects, including the antiinflammatory ones of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a problem in the management of inflammatory diseases and can be congenital as well as acquired. The strong proinflammatory cytokine TNF-alpha (TNF) induces an acute form of GCR, not only in mice, but also in several cell lines: e.g., in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-stimulated direct GR-dependent gene up-and down-regulation. We report that TNF has a significant and broad impact on this transcriptional performance of GR, but no impact on nuclear translocation, dimerization, or DNA binding capacity of GR. Proteome-wide proximitymapping (BioID), however, revealed that the GR interactome was strongly modulated by TNF. One GR cofactor that interacted significantly less with the receptor under GCR conditions is p300. NF kappa B activation and p300 knockdown both reduced direct transcriptional output of GR whereas p300 overexpression and NF kappa B inhibition reverted TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis was supported by FRET studies. This mechanism of GCR opens avenues for therapeutic interventions in GCR diseases.
Keywords
KAPPA-B, TRANSCRIPTIONAL ACTIVITY, PROTEIN INTERACTOMES, RESISTANCE, BINDING, ACETYLATION, MECHANISMS, CBP/P300, P300, MICE, transcription, regulation, genetics, mechanism

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MLA
Dendoncker, Karen, et al. “TNF-α Inhibits Glucocorticoid Receptor-Induced Gene Expression by Reshaping the GR Nuclear Cofactor Profile.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 116, no. 26, 2019, pp. 12942–51, doi:10.1073/pnas.1821565116.
APA
Dendoncker, K., Timmermans, S., Vandewalle, J., Eggermont, M., Lempiäinen, J., Paakinaho, V., … Libert, C. (2019). TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 116(26), 12942–12951. https://doi.org/10.1073/pnas.1821565116
Chicago author-date
Dendoncker, Karen, Steven Timmermans, Jolien Vandewalle, Melanie Eggermont, Joanna Lempiäinen, Ville Paakinaho, Evelien Van Hamme, et al. 2019. “TNF-α Inhibits Glucocorticoid Receptor-Induced Gene Expression by Reshaping the GR Nuclear Cofactor Profile.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116 (26): 12942–51. https://doi.org/10.1073/pnas.1821565116.
Chicago author-date (all authors)
Dendoncker, Karen, Steven Timmermans, Jolien Vandewalle, Melanie Eggermont, Joanna Lempiäinen, Ville Paakinaho, Evelien Van Hamme, Sylviane Dewaele, Sofie Vandevyver, Marlies Ballegeer, Jolien Souffriau, Lise Van Wyngene, Kelly Van Looveren, Tineke Vanderhaeghen, Rudi Beyaert, Karolien De Bosscher, Jorma J Palvimo, Marc Van Montagu, and Claude Libert. 2019. “TNF-α Inhibits Glucocorticoid Receptor-Induced Gene Expression by Reshaping the GR Nuclear Cofactor Profile.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 116 (26): 12942–12951. doi:10.1073/pnas.1821565116.
Vancouver
1.
Dendoncker K, Timmermans S, Vandewalle J, Eggermont M, Lempiäinen J, Paakinaho V, et al. TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2019;116(26):12942–51.
IEEE
[1]
K. Dendoncker et al., “TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile,” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 116, no. 26, pp. 12942–12951, 2019.
@article{8625614,
  abstract     = {{Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the therapeutic effects, including the antiinflammatory ones of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a problem in the management of inflammatory diseases and can be congenital as well as acquired. The strong proinflammatory cytokine TNF-alpha (TNF) induces an acute form of GCR, not only in mice, but also in several cell lines: e.g., in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-stimulated direct GR-dependent gene up-and down-regulation. We report that TNF has a significant and broad impact on this transcriptional performance of GR, but no impact on nuclear translocation, dimerization, or DNA binding capacity of GR. Proteome-wide proximitymapping (BioID), however, revealed that the GR interactome was strongly modulated by TNF. One GR cofactor that interacted significantly less with the receptor under GCR conditions is p300. NF kappa B activation and p300 knockdown both reduced direct transcriptional output of GR whereas p300 overexpression and NF kappa B inhibition reverted TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis was supported by FRET studies. This mechanism of GCR opens avenues for therapeutic interventions in GCR diseases.}},
  author       = {{Dendoncker, Karen and Timmermans, Steven and Vandewalle, Jolien and Eggermont, Melanie and Lempiäinen, Joanna and Paakinaho, Ville and Van Hamme, Evelien and Dewaele, Sylviane and Vandevyver, Sofie and Ballegeer, Marlies and Souffriau, Jolien and Van Wyngene, Lise and Van Looveren, Kelly and Vanderhaeghen, Tineke and Beyaert, Rudi and De Bosscher, Karolien and Palvimo, Jorma J and Van Montagu, Marc and Libert, Claude}},
  issn         = {{0027-8424}},
  journal      = {{PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}},
  keywords     = {{KAPPA-B,TRANSCRIPTIONAL ACTIVITY,PROTEIN INTERACTOMES,RESISTANCE,BINDING,ACETYLATION,MECHANISMS,CBP/P300,P300,MICE,transcription,regulation,genetics,mechanism}},
  language     = {{eng}},
  number       = {{26}},
  pages        = {{12942--12951}},
  title        = {{TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile}},
  url          = {{http://doi.org/10.1073/pnas.1821565116}},
  volume       = {{116}},
  year         = {{2019}},
}
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