Phosphorylation of the Retinoid X Receptor at the Omega loop, modulates the expression of retinoic-acid-target genes with a promoter context specificity

Bruck, Nathalie; Bastien, Julie; Bour, Gaétan; Tarrade, Anne; Plassat, Jean‐Luc; Bauer, Annie; Adam-Stitah, Sylvie; Rochette‐Egly, Cécile

doi:10.1016/j.cellsig.2004.12.006

Cited by 51 publications

(49 citation statements)

References 44 publications

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“…1A, *) consistent with phosphorylated RXR␣ (14,32,34). It is unlikely that a significant contribution is made from JNK-mediated modification of one or more RXR␣ partners and that RXR␣ is "dragged" out of the nucleus because of a partner effect, although this indirect route to nuclear export cannot be completely excluded (19,33).…”

Section: Discussionmentioning

confidence: 48%

Nuclear Export of Retinoid X Receptor α in Response to Interleukin-1β-mediated Cell Signaling

Zimmerman

Thevananther

Ghose

et al. 2006

Journal of Biological Chemistry

101

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As the obligate heterodimer partner to class II nuclear receptors, the retinoid X receptor ␣ (RXR␣) plays a vital physiological role in the regulation of multiple hepatic functions, including bile formation, intermediary metabolism, and endobiotic/xenobiotic detoxification. Many RXR␣-regulated genes are themselves suppressed in inflamed liver via unknown mechanisms, which constitute a substantial component of the negative hepatic acute phase response. In this study we show that RXR␣, generally considered a stable nuclear resident protein, undergoes rapid nuclear export in response to signals initiated by the pro-inflammatory cytokine interleukin-1␤ (IL-1␤), a central activator of the acute phase response. Within 30 min of exposure to IL-1␤, nuclear levels of RXR␣ are markedly suppressed in human liver-derived HepG2 cells, temporally coinciding with its appearance in the cytoplasm. The nuclear residence of RXR␣ is maintained by inhibiting c-jun N-terminal kinase (JNK, curcumin or SP600125) or CRM-1-mediated nuclear export (Leptomycin B). Pretreatment with the proteasome inhibitor MG132 blocks IL-1␤-mediated reductions in nuclear RXR␣ levels while increasing accumulation in the cytoplasm. Mutational studies identify one residue, serine 260, a JNK phosphoacceptor site whose phosphorylation status had an unknown role in RXR␣ function, as critical for IL-1␤-mediated nuclear export of transfected human RXR␣-green fluorescent fusion constructs. These findings indicate that inflammation-mediated cell signaling leads to rapid and profound reductions in nuclear RXR␣ levels, via a multistep, JNK-dependent mechanism involving Ser 260 , nuclear export, and proteasomal degradation. Thus, inflammation-meditated cell signaling targets RXR␣ for nuclear export and degradation; a potential mechanism that explains the broad suppression of RXR␣-dependent gene expression in the inflamed liver.After injury or infection, the liver participates in a program of modified gene expression known collectively as the acute phase response (APR) 2 (1). A wide variety of hepatic functions are altered during the APR, much of which occurs by cytokine-mediated activation or suppression of target gene transcription. Among the principal hepatic physiologic processes inhibited during the negative hepatic APR are genes involved in endobiotic/xenobiotic metabolism, glucose homeostasis, and bile formation, which then leads to cholestasis. Activation of the negative hepatic APR leads to cholestasis by decreasing bile salt synthesis (2), reducing canalicular bile salt export (3), and suppressing bile salt import, the latter of which occurs primarily by transcriptional down-regulation of the sodium-dependent taurocholate co-transporting polypeptide (Slc10A1) (4, 5). Recent evidence suggests that cytokine-mediated activation of cell signaling pathways during the APR leads to this coordinated response (6). One possibility is targeted repression of the essential heterodimer partner for type II nuclear receptor, RXR␣ (NR2B1), which is an attractive mechanism to ...

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Section: Discussionmentioning

confidence: 48%

Nuclear Export of Retinoid X Receptor α in Response to Interleukin-1β-mediated Cell Signaling

Zimmerman

Thevananther

Ghose

et al. 2006

Journal of Biological Chemistry

101

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“…An important hallmark of TRPM8 channel activity is requirement for PIP 2 (20,21), and, as was shown previously, in planar lipid bilayers, TRPM8 cannot be activated with its common agonists in the absence of this phosphoinositide (11, 13). We found that the presence of PIP 2 is also required for TRPM8 activation with testosterone.…”

Section: Testosterone-induced Trpm8 Activity In Hek-293 Cells-mentioning

confidence: 99%

“…The genomic actions of androgens are mediated by the androgen receptor (AR) 3 protein, a member of the nuclear receptor family of transcription factors (1,2). The steroid-AR complex is translocated to the nucleus, where it binds to promoters and stimulates gene expression (3).…”

mentioning

confidence: 99%

The TRPM8 Protein Is a Testosterone Receptor

Asuthkar

Demirkhanyan

Sun

et al. 2015

Journal of Biological Chemistry

103

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“…Indeed, p38MAPK phosphorylates RXR ␣ at three residues located in the NTD ( 144,145 ), but the consequences on transcription remain ill defi ned. P38MAPK also phosphorylates corepressors and coactivators to modulate their interaction with RARs and the dynamics of their exchanges.…”

Section: Other Phosphorylation Targets: Histones Coregulators and Omentioning

confidence: 99%

Vitamin A and retinoid signaling: genomic and nongenomic effects

Tanoury

Piskunov

Rochette‐Egly

2013

Journal of Lipid Research

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321

248

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Phosphorylation of the Retinoid X Receptor at the Omega loop, modulates the expression of retinoic-acid-target genes with a promoter context specificity

Cited by 51 publications

References 44 publications

Nuclear Export of Retinoid X Receptor α in Response to Interleukin-1β-mediated Cell Signaling

Nuclear Export of Retinoid X Receptor α in Response to Interleukin-1β-mediated Cell Signaling

The TRPM8 Protein Is a Testosterone Receptor

Vitamin A and retinoid signaling: genomic and nongenomic effects

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