Abstract
Here we have delineated regions of the retinoid X receptor alpha (RXRalpha) that are required for rexinoid (RXR agonist)-induced growth inhibition and apoptosis. Stable over-expression of RXRalpha in DT40 B lymphoma cells dramatically increased sensitivity to rexinoid-induced growth inhibition. By contrast, DT40 cells that over-expressed RXRalpha with a deletion of either the A/B or DNA binding domain (C domain) were resistant. We confirmed the importance of C domain integrity by point-mutating Cys(135) to Ser (C135S) to disrupt zinc-finger formation. Point mutating RXR Lys(201) to Thr and Arg(202) to Ala (KTRA) impairs RXR homodimer formation and does not affect RXR heterodimerization. When these mutated RXRs were over-expressed in DT40 cells, they failed to increase sensitivity to rexinoid. Over-expression did sensitize to growth inhibition by RAR and PPARgamma agonists. Over-expression of C135S mutated RXRalpha did not sensitize to RAR and PPARgamma agonists. Inhibitors of caspase-3 and/or caspase-9 blocked rexinoid-induced apoptosis, and activations of these caspases correlated with the ability of RXR mutants to induce cell death. These data show that the A/B and C domains of RXR and the ability of RXR to form homodimers are required for rexinoid-driven growth inhibition, caspase activation and subsequent apoptosis.
Original language | English |
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Pages (from-to) | 25-31 |
Number of pages | 7 |
Journal | The Journal of Steroid Biochemistry and Molecular Biology |
Volume | 112 |
Issue number | 1-3 |
DOIs | |
Publication status | Published - 1 Nov 2008 |
Keywords
- Rexinoid
- Homodimer
- Apoptosis
- Caspase
- Retinoid X receptor
- Growth inhibition