Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis

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Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis. / Qin, S; Okawa, Y; Atangan, L; Brown, Geoffrey; Chandraratna, R; Zhao, Yan.

In: The Journal of Steroid Biochemistry and Molecular Biology, Vol. 112, No. 1-3, 01.11.2008, p. 25-31.

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@article{3c84de3dad2b4f6a9752d2ea77028f08,
title = "Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis",
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.",
keywords = "Rexinoid, Homodimer, Apoptosis, Caspase, Retinoid X receptor, Growth inhibition",
author = "S Qin and Y Okawa and L Atangan and Geoffrey Brown and R Chandraratna and Yan Zhao",
year = "2008",
month = nov
day = "1",
doi = "10.1016/j.jsbmb.2008.08.001",
language = "English",
volume = "112",
pages = "25--31",
journal = "The Journal of Steroid Biochemistry and Molecular Biology",
issn = "0960-0760",
publisher = "Elsevier",
number = "1-3",

}

RIS

TY - JOUR

T1 - Integrities of A/B and C domains of RXR are required for rexinoid-induced caspase activations and apoptosis

AU - Qin, S

AU - Okawa, Y

AU - Atangan, L

AU - Brown, Geoffrey

AU - Chandraratna, R

AU - Zhao, Yan

PY - 2008/11/1

Y1 - 2008/11/1

N2 - 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.

AB - 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.

KW - Rexinoid

KW - Homodimer

KW - Apoptosis

KW - Caspase

KW - Retinoid X receptor

KW - Growth inhibition

U2 - 10.1016/j.jsbmb.2008.08.001

DO - 10.1016/j.jsbmb.2008.08.001

M3 - Article

C2 - 18761406

VL - 112

SP - 25

EP - 31

JO - The Journal of Steroid Biochemistry and Molecular Biology

JF - The Journal of Steroid Biochemistry and Molecular Biology

SN - 0960-0760

IS - 1-3

ER -