Physical and Functional Interactions between Cellular Retinoic Acid Binding Protein II and the Retinoic Acid-Dependent Nuclear Complex

Delva, Laurent; Bastie, Jean-Noël; Rochette‐Egly, Cécile; Kraïba, Radhia; Balitrand, N; Despouy, Gilles; Chambon, Pierre; Chomienne, Christine

doi:10.1128/mcb.19.10.7158

Cited by 171 publications

(164 citation statements)

References 48 publications

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“…Moreover, decreased protein expression of CRABP2 was significantly associated with shorter patient survival ( Figure 2C; see also Supplemental Table S4 at http://ajp.amjpathol.org). Because previous studies have shown that CRABP2 can translocate into the cell nucleus on RA binding, 15,22 we further assessed frequencies of nuclear CRABP2 staining ( Figure 2D) as a surrogate for an activated RA pathway and calculated potential associations between expression levels and clinical data. In agreement with our previous results, nuclear CRABP2 immunoreactivity decreased with tumor malignancy ( ϭ Ϫ0.14, P ϭ 0.04; Figure 2E), and low protein expression levels were significantly associated with shorter OS (Figure 2F; see also Supplemental Figure S1C and Supplemental Table S4 at http://ajp.…”

Section: Expression Of the Natural Ra Chaperone Protein Decreases Witmentioning

confidence: 99%

“…Previous studies have reported that FABP5 and CRABP2 can compete for cytoplasmic RA and translocate into the cell nucleus on RA binding. 15,22,26 Although cytoplasmic FABP5 serves as a chaperone protein for diverse metabolic compounds, nuclear translocation exclusively succeeds RA binding. 15 Indeed, nuclear FABP5 immunoreactivity was confirmed by confocal microscopy scanning in primary glioma tissues, suggesting an involvement of FABP5 in RA signaling ( Figure 5, B-D).…”

Section: Fabp5 a Potential Candidate For Alternative Ra Usage Is Stmentioning

confidence: 99%

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Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Campos

Centner

Bermejo

et al. 2011

The American Journal of Pathology

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Undifferentiated cell populations may influence tumor growth in malignant glioma. We investigated potential disruptions in the retinoic acid (RA) differentiation pathway that could lead to a loss of differentiation capacity, influencing patient prognosis. Expression of key molecules belonging to the RA differentiation pathway was analyzed in 283 astrocytic gliomas and was correlated with tumor proliferation, tumor differentiation, and patient survival. In addition, in situ concentrations of retinoids were measured in tumors, and RA signaling events were studied in vitro. Unlike other tumors, in gliomas expression of most RA signaling molecules increased with malignancy and was associated with augmented intratumoral retinoid levels in high-grade gliomas. Aberrantly expressed RA signaling molecules included i) the retinol-binding protein CRBP1, which facilitates cellular retinoid uptake; ii) ALDH1A1, capable of activating RA precursors; iii) the RA-degrading enzyme CYP26B1; and iv) the RA-binding protein FABP5, which can inhibit RA-induced differentiation. In contrast, expression of the RA-binding protein CRABP2, which fosters differentiation, was decreased in high-grade tumors. Moreover, expression of CRBP1 correlated with tumor proliferation, and FABP5 expression correlated with an undifferentiated tumor phenotype. CRBP1 and ALDH1A1 were independent prognostic markers for adverse patient survival. Our data indicate a complex and clinically relevant deregulation of RA signaling, which seems to be a central event in glioma pathogenesis.

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Section: Expression Of the Natural Ra Chaperone Protein Decreases Witmentioning

confidence: 99%

Section: Fabp5 a Potential Candidate For Alternative Ra Usage Is Stmentioning

confidence: 99%

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Campos

Centner

Bermejo

et al. 2011

The American Journal of Pathology

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“…The pSG5-based expression vectors for human (h) RAR␣1WT, hRAR␥1WT, and hRAR␥1S79A and mouse (m) RXR␣ were previously described, as well as the hRAR␤2-Luc and DR1-tk-CAT reporter genes (9,14,15). Vectors for hRAR␣S77A, S77E, P345G͞D346A, and L342T were constructed by double PCR amplification.…”

Section: Methodsmentioning

confidence: 99%

Cyclin H binding to the RARα activation function (AF)-2 domain directs phosphorylation of the AF-1 domain by cyclin-dependent kinase 7

Bour

Gaillard

Bruck

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The transcriptional activity of nuclear retinoic acid receptors (RARs), which act as RAR͞retinoid X receptor (RXR) heterodimers, depends on two activation functions, AF-1 and AF-2, which are targets for phosphorylations and synergize for the activation of retinoic acid target genes. The N-terminal AF-1 domain of RAR␣ is phosphorylated at S77 by the cyclin-dependent kinase (cdk)-activating kinase (CAK) subcomplex (cdk7͞cyclin H͞MAT1) of the general transcription factor TFIIH. Here, we show that phosphorylation of S77 governing the transcriptional activity of RAR␣ depends on cyclin H binding at a RAR␣ region that encompasses loop 8 -9 and the N-terminal tip of helix 9 of the AF-2 domain. We propose a model in which the structural constraints of this region control the architecture of the RAR͞RXR͞TFIIH complex and therefore the efficiency of RAR␣ phosphorylation by cdk7. To our knowledge, this study provides the first example of a cooperation between the AF-2 and AF-1 domains of RARs through a kinase complex.retinoic acid receptor ͉ transcription R etinoic acid (RA) regulates the expression of specific networks of genes through two families of nuclear receptors, the RA receptors (RARs) (␣, ␤, and ␥) and the retinoid X receptors (RXRs) (␣, ␤, and ␥), which act as ligand-dependent heterodimeric RAR͞RXR transcription activators (1, 2). The transcriptional activity of RARs depends on activation function (AF) 1 and AF-2, which synergize for the activation of RA target genes. The Cterminal AF-2 domain encompasses the ligand-binding domain (LBD), consisting of 11 ␣-helices (H1 and H3-H12) forming a compact structure (3, 4). Ligand binding promotes complex allosteric effects and conformational changes, the most striking one being the swing of helix 12 (5, 6), which leads to dissociation of corepressor complexes. It also generates an interaction surface for coactivators, which then recruit a battery of intermediary proteins, including chromatin remodellers and modifiers. They act in a coordinated and͞or combinatorial manner to decompact chromatin and direct the RNA polymerase II and the general transcription factors to the promoter (7), leading to the activation of the RA responsive genes.In the last several years, researchers have witnessed additional layers of regulation of transcription by RARs through their Nterminal AF-1 domain, which is targeted by phosphorylation processes. Indeed, the RAR␣1 and RAR␥1 isotypes are phosphorylated in their AF-1 domain at S77 and S79, respectively (Fig. 1A), by the cyclin-dependent kinase (cdk)-activating kinase (CAK) complex of the general transcription factor TFIIH (8, 9). TFIIH consists of 10 subunits (10) assembled into two subcomplexes: the core complex and CAK (composed of the cdk7, cyclin H, and MAT1 subunits). The key role of this phosphorylation process in the RA response has been highlighted by studies performed with patients carrying a mutation in one subunit [XPD (xeroderma pigmentosum group D)] of the core of TFIIH (11). This mutation altering the architecture of TFIIH resu...

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“…Cells were analysed after 2 and 4 days in the absence (À) or presence of ATRA 10 À6 M ( þ ). Nuclear extracts from cells were obtained as described previously (Delva et al, 1999) and quantified by the biocinchoninic acid (BCA) protein assay (Pierce, Rockford, IL, USA). Proteins were run in 10% polyacrylamide gels and transferred to a nitrocellulose membrane.…”

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confidence: 99%

Epigenetic patterns of the retinoic acid receptor β2 promoter in retinoic acid-resistant thyroid cancer cells

et al. 2007

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Physical and Functional Interactions between Cellular Retinoic Acid Binding Protein II and the Retinoic Acid-Dependent Nuclear Complex

Cited by 171 publications

References 48 publications

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Aberrant Expression of Retinoic Acid Signaling Molecules Influences Patient Survival in Astrocytic Gliomas

Cyclin H binding to the RARα activation function (AF)-2 domain directs phosphorylation of the AF-1 domain by cyclin-dependent kinase 7

Epigenetic patterns of the retinoic acid receptor β2 promoter in retinoic acid-resistant thyroid cancer cells

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