Heterogeneous nuclear ribonucleoprotein K is a novel regulator of androgen receptor translation.
Heterogeneous nuclear ribonucleoprotein K is a novel regulator of androgen receptor translation.
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DOI：
10.1158/0008-5472.can-08-2308
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Freeman MR
中科院分区：
文献类型：
--
作者：
Mukhopadhyay NK;Kim J;Cinar B;Ramachandran A;Hager MH;Di Vizio D;Adam RM;Rubin MA;Raychaudhuri P;De Benedetti A;Freeman MR
雄激素受体（AR）在前列腺癌（PCa）中的表达调控仍然知之甚少。先前研究表明，PCa细胞中表皮生长因子受体（EGFR）的激活通过涉及AR mRNA 5′-非翻译区（5′-UTR）的雷帕霉素敏感性转录后机制降低AR表达。在寻找EGFR/PI 3-激酶/Akt/mTOR通路中调节AR的中间体的过程中，我们通过质谱分析富含脂筏的亚细胞组分中的Akt免疫复合物，鉴定了核酸结合蛋白，异质核核糖核蛋白K（hnRNP-K）。我们在这里表明，hnRNP-K是一种新的AR mRNA翻译抑制剂，调节雄激素反应基因的表达和PCa细胞增殖。在AR mRNA 5′-UTR中发现了一个参与下调AR蛋白水平的功能性hnRNP-K结合位点。进一步的分析表明，hnRNP-K也能够在5′-UTR缺失的情况下抑制AR翻译，这与AR开放阅读框内和3′-UTR中存在额外的预测hnRNP-K结合位点一致。人前列腺癌组织微阵列的免疫组化分析显示，hnRNP-K表达和AR蛋白水平之间的负相关性器官局限性前列腺癌肿瘤和细胞质hnRNP-K的转移显着下降，尽管在转移性肿瘤中的hnRNP-K水平的整体增加。这些数据表明hnRNP-K对AR的翻译抑制可能发生在器官局限性肿瘤中，但可能在转移中水平降低。HnRNP-K是第一个被鉴定的直接与AR翻译装置相互作用并调节AR翻译装置的蛋白质。
Regulation of androgen receptor (AR) expression in prostate cancer (PCa) is still poorly understood. Activation of the epidermal growth factor receptor (EGFR) in PCa cells was previously shown to lower AR expression by a rapamycin-sensitive, post-transcriptional mechanism involving the AR mRNA 5′-untranslated region (5′-UTR). In a search for an intermediate within the EGFR/PI3-kinase/Akt/mTOR pathway that regulates AR at this site, we identified the nucleic acid binding protein, heterogeneous nuclear ribonucleoprotein K (hnRNP-K), by mass spectrometric analysis of Akt immune complexes from lipid raft-enriched subcellular fractions. We show here that hnRNP-K is a novel inhibitor of AR mRNA translation that regulates androgen-responsive gene expression and PCa cell proliferation. A functional hnRNP-K binding site involved in down-regulating AR protein levels was identified in the AR mRNA 5′-UTR. Further analysis revealed that hnRNP-K is also able to inhibit AR translation in the absence of the 5′-UTR, consistent with the presence of additional predicted hnRNP-K binding sites within the AR open reading frame and in the 3′-UTR. Immunohistochemical analysis of a human PCa tissue microarray revealed an inverse correlation between hnRNP-K expression and AR protein levels in organ-confined PCa tumors and a substantial decline in cytoplasmic hnRNP-K in metastases, despite an overall increase in hnRNP-K levels in metastatic tumors. These data suggest that translational inhibition of AR by hnRNP-K may occur in organ-confined tumors but possibly at a reduced level in metastases. HnRNP-K is the first protein identified that directly interacts with and regulates the AR translational apparatus.