Fernandez-Marrero Yuniel, Bachmann Daniel, Lauber Emanuel, Kaufmann Thomas
Institute of Pharmacology, Faculty of Medicine, University of Bern, Inselspital, INO-F, 3010 Bern, Switzerland.
Institute of Pharmacology, Faculty of Medicine, University of Bern, Inselspital, INO-F, 3010 Bern, Switzerland.
iScience. 2018 Nov 30;9:461-474. doi: 10.1016/j.isci.2018.11.005. Epub 2018 Nov 10.
BCL-2-related ovarian killer (BOK) is a pro-apoptotic BAX-like member of the BCL-2 family with suggested tumor suppressor activity. The molecular mechanisms regulating BOK expression are poorly understood and fail to explain a frequent lack of concordance between protein and transcript levels. Here, we describe a potent post-transcriptional mechanism that negatively regulates BOK expression mediated by conserved (AU/U)-rich elements within its 3' UTR. Using proteomics approaches we identified TRIM28 as a key component associating with U-rich elements in the human BOK 3' UTR, resulting in a dramatic reduction of BOK expression. TRIM28 is overexpressed in several cancers, correlating with poor patient outcome, whereas the BOK locus is frequently deleted or its expression downregulated in human cancers. Data mining indicated that, for certain cancers, high TRIM28 and low BOK expression are significantly correlated in the stratum of patients with the worst survival, suggesting that this mechanism might be of potential therapeutic value.
BCL-2相关卵巢杀手蛋白（BOK）是BCL-2家族中一种具有促凋亡作用的BAX样成员，具有潜在的肿瘤抑制活性。目前对调控BOK表达的分子机制了解甚少，也无法解释蛋白质水平和转录本水平之间经常出现的不一致现象。在此，我们描述了一种有效的转录后机制，该机制通过其3'非翻译区内保守的富含（AU/U）元件介导对BOK表达的负调控。利用蛋白质组学方法，我们鉴定出TRIM28是与人BOK 3'非翻译区富含U元件相关的关键成分，导致BOK表达显著降低。TRIM28在多种癌症中过表达，与患者预后不良相关，而BOK基因座在人类癌症中经常缺失或其表达下调。数据挖掘表明，对于某些癌症，在生存最差的患者群体中，TRIM28高表达和BOK低表达显著相关，这表明该机制可能具有潜在的治疗价值。
