Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen
Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen
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DOI：
10.1038/onc.2013.306
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发表时间：
2014-06-26
期刊：
影响因子：
8
通讯作者：
Robson, T.
中科院分区：
文献类型：
--
作者：
Donley, C.;McClelland, K.;Robson, T.
FKBPL参与了与癌症相关的过程，包括调节肿瘤生长和血管生成，高水平的FKBPL预示着患者生存的改善。因此，了解FKBPL水平在细胞内是如何控制的是至关重要的。我们已经确定了RBCK1作为一种FKBPL相互作用蛋白的新角色，它通过泛素化在翻译后水平上调节FKBPL的稳定性。RBCK1和FKBPL都被17-β-雌二醇上调，并在热休克蛋白90伴侣复合体中与雌激素受体-α(ERα)相互作用。此外，FKBPL和RBCK1在雌激素反应基因PS2的启动子上与ERα结合，调节PS2水平。稳定高表达RBCK1的McF-7克隆的增殖受到抑制，FKBPL和p21表达水平升高。此外，这些克隆对他莫昔芬治疗具有抵抗力，这表明RBCK1可能是内分泌治疗反应的预测标记物。使用靶向小干扰RNA敲除RBCK1导致细胞增殖增加，并增加了对他莫昔芬治疗的敏感性。此外，为了支持我们的体外数据，对mRNA微阵列数据集的分析表明，高水平的FKBPL和RBCK1与患者存活率的增加相关，而高RBCK1预示着对他莫昔芬的不良反应。我们的发现支持RBCK1在调节FKBPL中的作用，对雌激素受体信号、细胞增殖和内分泌治疗的反应具有重要意义。
FKBPL has been implicated in processes associated with cancer, including regulation of tumor growth and angiogenesis with high levels of FKBPL prognosticating for improved patient survival. Understanding how FKBPL levels are controlled within the cell is therefore critical. We have identified a novel role for RBCK1 as an FKBPL-interacting protein, which regulates FKBPL stability at the post-translational level via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-beta-estradiol and interact within heat shock protein 90 chaperone complexes, together with estrogen receptor-alpha (ER alpha). Furthermore, FKBPL and RBCK1 associate with ER alpha at the promoter of the estrogen responsive gene, pS2, and regulate pS2 levels. MCF-7 clones stably overexpressing RBCK1 were shown to have reduced proliferation and increased levels of FKBPL and p21. Furthermore, these clones were resistant to tamoxifen therapy, suggesting that RBCK1 could be a predictive marker of response to endocrine therapy. RBCK1 knockdown using targeted small interfering RNA resulted in increased proliferation and increased sensitivity to tamoxifen treatment. Moreover, in support of our in vitro data, analysis of mRNA microarray data sets demonstrated that high levels of FKBPL and RBCK1 correlated with increased patient survival, whereas high RBCK1 predicted for a poor response to tamoxifen. Our findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy.