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Janus kinase 2 - A novel negative regulator of estrogen receptor α function

机译：Janus激酶2-雌激素受体α功能的新型负调节剂

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Estrogen receptor α (ERα) functions as a transcription factor to regulate a wide range of cellular activities in response to 17β-estradiol (E2). The regulation of ERα transcriptional activity is highly complex and not yet fully understood. In this respect, recent studies have highlighted the importance of certain cellular protein kinases. To identify novel protein kinases regulating ERα activity, we performed a high-throughput siRNA screening in combination with a luciferase reporter assay in an ERα positive breast cancer cell line. Among the vast majority of potential positive regulators, we found Janus kinase 2 (JAK2), a member of the Janus kinase family of non-receptor tyrosine kinases, to have a negative regulatory effect on E2 induced luciferase activity. In addition, silencing of JAK2 resulted in increased expression of endogenous ERα target genes, pS2 and GREB1. In an attempt to understand the mechanism underlying JAK2 mediated regulation of ERα transcriptional activity, we found that JAK2 negatively regulates ERα protein level. Gene expression analysis revealed no significant influence of JAK2 on ERα mRNA level. Subsequently, a role of JAK2 in regulating ERα protein degradation was analyzed. Inhibition of the lysosome did not alter JAK2 mediated downregulation of ERα. In contrast, using proteasome inhibitors MG132 and lactacystin, we demonstrated that JAK2 governs ERα protein stability via the ubiquitin-proteasome pathway. In contrast to JAK2, the two other members of the JAK family expressed in the breast (JAK1 and TYK2) had no influence on ERα function. In addition, we found that prolonged E2 treatment upregulates JAK2 mRNA and protein levels. These results suggest a novel negative regulation of ERα activity and protein by JAK2 in breast cancer cells and indicate a potential new cross-talk.
机译：雌激素受体α（ERα）作为转录因子来调节对17β-雌二醇（E2）的各种细胞活动。 ERα转录活性的调节高度复杂，尚未完全了解。在这方面，最近的研究强调了某些细胞蛋白激酶的重要性。为了鉴定调节ERα活性的新型蛋白激酶，我们在ERα阳性乳腺癌细胞系中结合荧光素酶报告基因分析进行了高通量siRNA筛选。在绝大多数潜在的正调节剂中，我们发现Janus激酶2（JAK2）（非受体酪氨酸激酶的Janus激酶家族的成员）对E2诱导的荧光素酶活性具有负调节作用。此外，JAK2沉默导致内源性ERα靶基因pS2和GREB1的表达增加。在试图了解JAK2介导的ERα转录活性调控机制的过程中，我们发现JAK2负调控ERα蛋白水平。基因表达分析表明，JAK2对ERαmRNA水平无明显影响。随后，分析了JAK2在调节ERα蛋白降解中的作用。溶酶体的抑制不会改变JAK2介导的ERα下调。相比之下，我们使用蛋白酶体抑制剂MG132和lactyacystin，证明JAK2通过泛素-蛋白酶体途径控制ERα蛋白的稳定性。与JAK2相比，在乳房中表达的JAK家族的其他两个成员（JAK1和TYK2）对ERα功能没有影响。此外，我们发现长时间的E2治疗会上调JAK2 mRNA和蛋白质水平。这些结果表明，JAK2在乳腺癌细胞中对ERα活性和蛋白质产生了新的负调控，并表明了潜在的新串扰。

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