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

被引：47

作者：

Dendoncker, Karen ^{[1
,2
]}

Timmermans, Steven ^{[1
,2
]}

Vandewalle, Jolien ^{[1
,2
]}

Eggermont, Melanie ^{[1
,2
]}

Lempiainen, Joanna ^{[3
]}

Van Hamme, Evelien ^{[4
]}

Dewaele, Sylviane ^{[1
,2
]}

Vandevyver, Sofie ^{[1
,2
]}

Ballegeer, Marlies ^{[1
,2
]}

Souffriau, Jolien ^{[1
,2
]}

Van Wyngene, Lise ^{[1
,2
]}

Van Looveren, Kelly ^{[1
,2
]}

Vanderhaeghen, Tineke ^{[1
,2
]}

Beyaert, Rudi ^{[1
,2
]}

De Bosscher, Karolien ^{[5
,6
]}

Palvimo, Jorma J. ^{[3
]}

Van Montagu, Marc ^{[7
,8
,9
]}

Libert, Claude ^{[1
,2
]}

机构：

[1] VIB Ctr Inflammat Res, Mouse Genet Inflammat, B-9052 Ghent, Belgium

[2] Univ Ghent, Dept Biomed Mol Biol, B-9052 Ghent, Belgium

[3] Univ Eastern Finland, Inst Biomed, Kuopio 70211, Finland

[4] VIB Ctr Inflammat Res, Bio Imaging Core, B-9052 Ghent, Belgium

[5] VIB, Med Biotechnol Ctr, B-9000 Ghent, Belgium

[6] Univ Ghent, Dept Biochem, B-9000 Ghent, Belgium

[7] Univ Ghent, Dept Plant Biotechnol & Bioinformat, B-9052 Ghent, Belgium

[8] VIB, Ctr Plant Syst Biol, B-9052 Ghent, Belgium

[9] VIB, Int Plant Biotechnol Outreach, B-9052 Ghent, Belgium

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2019年 / 116卷 / 26期

关键词：

transcription; regulation; genetics; mechanism; KAPPA-B; TRANSCRIPTIONAL ACTIVITY; PROTEIN INTERACTOMES; RESISTANCE; BINDING; ACETYLATION; MECHANISMS; CBP/P300; P300; MICE;

D O I：

10.1073/pnas.1821565116

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：12942 / 12951

页数：10

共 49 条

[1] Glucocorticoid receptor dimers control intestinal STAT1 and TNF-induced inflammation in mice [J].