Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RARalpha) and oncogenic RARalpha fusion proteins.
Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor alpha (RARalpha) and oncogenic RARalpha fusion proteins.
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发表时间：
1999
影响因子：
11.1
通讯作者：
J. Zhu;M. Giannı́;E. Kopf;N. Honoré;M. Chelbi-alix;M. Koken;F. Quignon;C. Rochette-Egly;H. de Thé
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作者：
J. Zhu;M. Giannı́;E. Kopf;N. Honoré;M. Chelbi-alix;M. Koken;F. Quignon;C. Rochette-Egly;H. de Thé
分析视黄酸（RA）诱导急性早幼粒细胞白血病（APL）中早幼粒细胞白血病/视黄酸受体α（PML/RARα）分解代谢的途径，我们发现，除了半胱天冬酶介导的PML/RARα裂解外，RA还触发PML/RARα和RARα的降解。类似地，在非 APL 细胞中，RA 直接将 RARα 和 RARα 融合物靶向蛋白酶体降解途径。特定激动剂激活 RARα 或 RXRα 会诱导两种蛋白质的降解。相反，RARα 中的突变消除了异二聚体的形成和 DNA 结合，从而阻止了 RARα 和 RXRα 的降解。 RARα DNA 结合域或 AF-2 转录激活区域的突变也会损害 RARα 分解代谢。因此，我们的结果将转录激活与受体分解代谢联系起来，并表明核受体配体的转录上调可能是一种允许靶基因持续激活的反馈机制。
Analyzing the pathways by which retinoic acid (RA) induces promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) catabolism in acute promyelocytic leukemia (APL), we found that, in addition to caspase-mediated PML/RARalpha cleavage, RA triggers degradation of both PML/RARalpha and RARalpha. Similarly, in non-APL cells, RA directly targeted RARalpha and RARalpha fusions to the proteasome degradation pathway. Activation of either RARalpha or RXRalpha by specific agonists induced degradation of both proteins. Conversely, a mutation in RARalpha that abolishes heterodimer formation and DNA binding, blocked both RARalpha and RXRalpha degradation. Mutations in the RARalpha DNA-binding domain or AF-2 transcriptional activation region also impaired RARalpha catabolism. Hence, our results link transcriptional activation to receptor catabolism and suggest that transcriptional up-regulation of nuclear receptors by their ligands may be a feedback mechanism allowing sustained target-gene activation.