کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1992857 | 1541063 | 2008 | 7 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis](/preview/png/1992857.png)
Here we have delineated regions of the retinoid X receptor α (RXRα) that are required for rexinoid (RXR agonist)-induced growth inhibition and apoptosis. Stable over-expression of RXRα in DT40 B lymphoma cells dramatically increased sensitivity to rexinoid-induced growth inhibition. By contrast, DT40 cells that over-expressed RXRα 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 Cys135 to Ser (C135S) to disrupt zinc-finger formation. Point mutating RXR Lys201 to Thr and Arg202 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 PPARγ agonists. Over-expression of C135S mutated RXRα did not sensitize to RAR and PPARγ 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.
Journal: The Journal of Steroid Biochemistry and Molecular Biology - Volume 112, Issues 1–3, November 2008, Pages 25–31