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

Abstract

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.

Vitamin A and retinoid signaling: genomic and nongenomic effects

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The Estrogen-responsive B Box Protein Is a Novel Regulator of the Retinoid Signal

“…Most nuclear hormone receptors are phosphoproteins, and phosphorylation is a potent regulator of nuclear receptor function. Depending on the receptor, phosphorylation can regulate receptor DNA binding, dimerization, coactivator recruitment, and transactivation (22)(23)(24)(25)(26). These findings led us to hypothesize that the retinoid anti-cancer effect may be determined by other proteins that undergo post-translational modification following retinoid treatment of cancer cells, and, moreover, that such changes in co-regulator proteins may represent mechanisms for overcoming retinoid resistance in cancer cells.…”

RXR, un cofacteur essentiel à la transformation dans les leucémies aiguës promyélocytaires

“…Trois résidus du domaine amino-terminal de RXRa, les sérines 61 et 75 et la thréonine 87, sont phosphorylés en réponse à l'AR et à différents stress génotoxiques. Cette étape est nécessaire à la coopération entre RXRa et RARg pour une transcription maximale des gènes cibles [14,15]. Enfin, en réponse à des signaux de stress géno-toxiques, on observe aussi une phosphorylation par JNK de la sérine 265 dans le domaine AF2 de mRXRa, ce qui entraîne une diminution de la transcription des gènes cibles [11].…”