Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation.
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Mann KK, Padovani AM, Guo Q, Colosimo AL, Lee HY, Kurie JM, Miller WH Jr
Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRalpha phosphorylation.
J Clin Invest. 2005 Oct;115(10):2924-33. Epub 2005 Sep 22.
- PubMed ID
- 16184197 [ View in PubMed]
- Abstract
We have previously published that 2 proven treatments for acute promyelocytic leukemia, As2O3 and retinoic acid, can be antagonistic in vitro. We now report that As2O3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor alpha (RXRalpha). As2O3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRalpha. We further show that As2O3 inhibits expression of several target genes of RXRalpha partners. Phosphorylation of RXRalpha has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As2O3 phosphorylated RXRalpha in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As2O3-induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As2O3-induced RXRalpha phosphorylation and blocked the effects of As2O3 on RXRalpha-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRalpha-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As2O3 as well as into molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Arsenic trioxide Cytochrome P450 3A4 Protein Humans UnknownInhibitorDetails - Pharmaco-transcriptomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Tretinoin Approved Investigational Nutraceutical CEBPE 1053 upregulated Tretinoin results in increased expression of CEBPE mRNA 14q11.2 Tretinoin Approved Investigational Nutraceutical RARB 5915 upregulated Tretinoin results in increased expression of RARB mRNA 3p24.2 Cholecalciferol Approved Nutraceutical CYP24A1 1591 upregulated Cholecalciferol results in increased expression of CYP24A1 mRNA 20q13.2 - Pharmaco-proteomics
Drug Drug Groups Gene Gene ID Change Interaction Chromosome Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1 Rifampicin Approved CYP3A4 1576 increased Rifampin results in increased expression of CYP3A4 protein 7q22.1