Loading…

Arsenic trioxide inhibits nuclear receptor function via SEK1/JNK-mediated RXRα phosphorylation

We have previously published that 2 proven treatments for acute promyelocytic leukemia, As 2 O 3 and retinoic acid, can be antagonistic in vitro. We now report that As 2 O 3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize wi...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of clinical investigation 2005-10, Vol.115 (10), p.2924-2933
Main Authors: Mann, Koren K., Padovani, Alessandra M.S., Guo, Qi, Colosimo, April L., Lee, Ho-Young, Kurie, Jonathan M., Jr, Wilson H. Miller
Format: Article
Language:English
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:We have previously published that 2 proven treatments for acute promyelocytic leukemia, As 2 O 3 and retinoic acid, can be antagonistic in vitro. We now report that As 2 O 3 inhibits ligand-induced transcription of the retinoic acid receptor, as well as other nuclear receptors that heterodimerize with the retinoid X receptor α (RXRα). As 2 O 3 did not inhibit transactivation of the estrogen receptor or the glucocorticoid receptor, which do not heterodimerize with RXRα. We further show that As 2 O 3 inhibits expression of several target genes of RXRα partners. Phosphorylation of RXRα has been reported to inhibit nuclear receptor signaling, and we show by in vivo labeling and phosphoamino acid detection that As 2 O 3 phosphorylated RXRα in the N-terminal ABC region exclusively on serine residues. Consistent with our previous data implying a role for JNK in As 2 O 3 -induced apoptosis, we show that pharmacologic or genetic inhibition of JNK activation decreased As 2 O 3 -induced RXRα phosphorylation and blocked the effects of As 2 O 3 on RXRα-mediated transcription. A mutational analysis indicated that phosphorylation of a specific serine residue, S32, was primarily responsible for inhibition of RXRα-mediated transcription. These data may provide some insight into the rational development of chemotherapeutic combinations involving As 2 O 3 as well as into molecular mechanisms of arsenic-induced carcinogenesis resulting from environmental exposure.
ISSN:0021-9738
DOI:10.1172/JCI23628