• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Oncogene >Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression
【24h】

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

机译：晚期前列腺癌中雄激素受体激活的机制：差异共激活子募集和基因表达

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Prostate tumour growth depends on androgens; hence treatment includes androgen ablation and anti-androgens. Eventually tumours progress and in approximately 30% of patients this is associated with mutation of the androgen receptor. Several receptor variants associated with advanced disease show promiscuous activation by other hormones and anti-androgens. Such loss of specificity could promote receptor activation, hence tumour growth, in the absence of conventional ligands, explaining therapy failure. We aimed to elucidate mechanisms by which alternative ligands promote receptor activation. The three most commonly identified variants in tumours (with amino-acid substitutions H874Y, T877A and T877S) and wild-type receptor showed differences in co-activator recruitment dependent upon ligand and the interaction motif utilized. Co-expression and knockdown of co-activators that bind via leucine or phenylalanine motifs, combined with chromatin immunoprecipitation and quantitative PCR, revealed these preferences extend to co-activator recruitment in vivo and affect receptor activity at the transcriptional level, with subsequent effects on target gene regulation. The findings suggest that mutant receptors, activated by alternative ligands, drive growth via different mechanisms to androgen-activated wild-type receptor. Tumours may hence behave differently dependent upon any androgen receptor mutation present and what ligand is driving growth, as distinct subsets of genes may be regulated.
机译：前列腺肿瘤的生长依赖于雄激素。因此治疗包括雄激素消融和抗雄激素。最终肿瘤进展，大约30％的患者与雄激素受体的突变有关。与晚期疾病相关的几种受体变体显示出其他激素和抗雄激素的混杂激活。在缺乏常规配体的情况下，这种特异性丧失可能促进受体活化，从而促进肿瘤生长，从而解释了治疗失败的原因。我们旨在阐明替代配体促进受体激活的机制。肿瘤中三个最常见的变异体（氨基酸替换为H874Y，T877A和T877S）和野生型受体在共激活因子募集方面表现出差异，这取决于配体和所利用的相互作用基序。通过亮氨酸或苯丙氨酸基序结合的共激活子的共表达和敲除，结合染色质免疫沉淀和定量PCR，揭示了这些偏好延伸到体内共激活子募集并在转录水平上影响受体活性，随后对靶标产生影响基因调控。这些发现表明，由其他配体激活的突变受体通过不同的机制驱动生长，从而激活雄激素激活的野生型受体。肿瘤可能因此而表现出不同的行为，这取决于存在的任何雄激素受体突变以及什么配体正在驱动生长，因为可以调节基因的不同子集。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号