Phosphorylation by p38MAPK and recruitment of SUG-1 are required for RA-induced RARgamma degradation and transactivation

Giannı̀, Maurizio; Bauer, Annie; Garattini, Enrico; Chambon, Pierre; Rochette‐Egly, Cécile

doi:10.1093/emboj/cdf374

Cited by 139 publications

(147 citation statements)

References 59 publications

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“…Treatment of RAR␥-transfected cells with SB203580, an inhibitor of the p38 MAPK known to phosphorylate Ser-77 and Ser-79 (13), resulted in disappearance of the slow migrating RAR␥ band (Fig. 6A), suggesting that RAR␥ was mainly phosphorylated by the p38 MAPK in cells, consistent with previous results (13). We also examined the effect of ligand binding and RXR␣ heterodimerization on RAR␥ phosphorylation.…”

Section: N-terminal A/b Domain Of Rar␥ Is Crucial For Its Cytoplasmsupporting

confidence: 86%

“…The serine residues (Ser-77 and Ser-79 in human RAR␥1) in the A/B domain of RAR␥ can be phosphorylated by cdk7 and p38 MAPK (12,13). To determine whether they were responsible for RAR␥ phosphorylation, we constructed a RAR␥ mutant, in which Ser-77 and Ser-79 were mutated to alanine.…”

Section: N-terminal A/b Domain Of Rar␥ Is Crucial For Its Cytoplasmmentioning

confidence: 99%

“…Dimerization interfaces that largely mediate heterodimerization of RXR␣ with RARs have been mapped to regions in the C terminus, corresponding to helices 9 and 10 in the canonical nuclear receptor LBD structure (10,11). The N-terminal A/B domain contains conserved serine residues, which belong to consensus phosphorylation sites for prolinedependent protein kinases such as cyclin-dependent kinases (Cdks) and the mitogen-activated protein kinases (MAPKs) (12)(13)(14), and phosphorylation of these sites can regulate RAR transactivation (15). Phosphorylation of the A/B domain of RAR␥ is indispensable for differentiation of F9 cells upon RA and cAMP treatment (16), whereas RAR␣ binds to CDK-acti-vating kinase, resulting in an enhanced CDK-activating kinase activity and cell proliferation (17).…”

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confidence: 99%

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A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

Han

Zhou

Kim

et al. 2009

Journal of Biological Chemistry

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Recent evidence suggests that extranuclear action of retinoid receptors is involved in mediating the pleiotropic effects of retinoids. However, whether they reside in the cytoplasm remains elusive. Here, we showed that retinoic acid receptor-␥ (RAR␥) was cytoplasmic in confluent cells, or when cells were released from serum depletion or treated with growth factors. In studying the regulation of RAR␥ subcellular localization, we observed that ectopically overexpressed RAR␥ was mainly cytoplasmic irrespective of serum concentration and cell density. The cytoplasmic retention of RAR␥ was inhibited by ligand retinoic acid (RA). In addition, coexpression of retinoid X receptor-␣ (RXR␣) resulted in nuclear localization of RAR␥ through their heterodimerization. Mutagenesis studies revealed that a C-terminal fragment of RXR␣ potently prevents RA-induced RAR␥ nuclear localization and transcriptional function. Furthermore, our results showed that the cytoplasmic retention of RAR␥ was due to the presence of its unique N-terminal A/B domain, which was subject to regulation by p38 MAPK-mediated phosphorylation. Deletion or mutation of the N-terminal A/B domain largely impaired its cytoplasmic localization. Together, our data demonstrate that the subcellular localization of RAR␥ is regulated by complex interactions among ligand binding, receptor phosphorylation, and receptor dimerizations.

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Section: N-terminal A/b Domain Of Rar␥ Is Crucial For Its Cytoplasmsupporting

confidence: 86%

Section: N-terminal A/b Domain Of Rar␥ Is Crucial For Its Cytoplasmmentioning

confidence: 99%

mentioning

confidence: 99%

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A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

Han

Zhou

Kim

et al. 2009

Journal of Biological Chemistry

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“…RARs are phosphorylated at one residue (Ser 77 in RARa1 and Ser 68 in RARg2) Bastien et al, 2000) by cdk7/ cyclin H associated to the general transcription factor TFIIH. In response to RA, RARg2 is also phosphorylated by p38MAPK at the nearby serine residue (S66) (Gianni et al, 2002a). These phosphorylation processes are crucial for RAR activity.…”

Section: Introductionmentioning

confidence: 99%

Retinoic acid and arsenic trioxide cooperate for apoptosis through phosphorylated RXR alpha

et al. 2005

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Arsenite trioxide (As 2 O 3 ) induces apoptosis in several cell lines by disturbing key signal transduction pathways through its oxidative properties. Here, we report that As 2 O 3 also induces the phosphorylation of the retinoid receptor RXRa, subsequent to oxidative damages and the activation of the stress-activated protein kinases cascade (JNKs). We also report that RA amplifies both As 2 O 3 -induced phosphorylation of RXRa and apoptosis. Taking advantage of 'rescue' F9 cell lines expressing RXRa mutated at its phosphorylation sites, in an RXRa null background, we provide evidence that RXRa is a key element involved in that potentiating effect. Finally, we demonstrate that As 2 O 3 also abrogates the transactivation of RA-target genes.

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“…The new conformation generates an interaction surface for coactivators (9), which then recruit multiprotein complexes and lead to the activation of responsive genes (10,11). Through this surface, RARs also interact with SUG-1 (12), which belongs to the 19 S regulatory complex of the 26 S proteasome (13).…”

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confidence: 99%

The AF-1 and AF-2 Domains of RARγ2 and RXRα Cooperate for Triggering the Transactivation and the Degradation of RARγ2/RXRα Heterodimers

Giannı̀¹,

Tarrade²,

Nigro

et al. 2003

Journal of Biological Chemistry

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In eukaryotic cells, liganded RAR␥2/RXR␣ heterodimers activate the transcription of retinoic acid (RA) target genes and then are degraded through the ubiquitin-proteasome pathway. In this study, we dissected the role of the RAR␥2 and RXR␣ partners as well as of their respective AF-1 and AF-2 domains in the processes of transactivation and degradation. RAR␥2 is the "engine" initiating transcription and its own degradation subsequent to ligand binding. Integrity of its AF-2 domain and phosphorylation of its AF-1 domain are required for both the degradation and the transactivation of the receptor. Deletion of the whole AF-1 domain does not impair these processes but shifts the receptor toward other proteolytic pathways through RXR␣. In contrast, RXR␣ plays only a modulatory role, cooperating with RAR␥2 through its AF-2 domain and its phosphorylated AF-1 domain in both the transcription activity and the degradation of the RAR␥2/RXR␣ heterodimers. Our results underline that the AF-1 and AF-2 domains of each heterodimer partner cooperate with one other and that this cooperation is relevant for both the transcription and degradation processes.

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Phosphorylation by p38MAPK and recruitment of SUG-1 are required for RA-induced RARgamma degradation and transactivation

Cited by 139 publications

References 59 publications

A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

A Unique Cytoplasmic Localization of Retinoic Acid Receptor-γ and Its Regulations

Retinoic acid and arsenic trioxide cooperate for apoptosis through phosphorylated RXR alpha

The AF-1 and AF-2 Domains of RARγ2 and RXRα Cooperate for Triggering the Transactivation and the Degradation of RARγ2/RXRα Heterodimers

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