*Physiology and Experimental Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Biochem J. 2014 Aug 1;461(3):391-402. doi: 10.1042/BJ20140066.
BOK (BCL-2-related ovarian killer) is a member of the pro-apoptotic BCL-2 family that is highly expressed in the human placenta. BOK excess causes increased trophoblast autophagy and apoptosis in pre-eclampsia, a pathological condition of hypoxia and oxidative stress. In the present study, we identified an HRE (hypoxia-response element) at the junction of exon-1 and intron-1 (+229 to +279) in the human BOK gene, as well as an antisense transcript driven by a promoter located in intron-2. The isolated BOK-HRE bound hypoxia-inducible HIF (hypoxia-inducible factor) proteins in vitro as well as in trophoblastic JEG3 cells and was functional in its natural position as well as in front of a heterologous promoter. Being a reverted repeat, the BOK-HRE functioned in both orientations. This directionless feature of the BOK-HRE facilitates hypoxia regulation via HIF of both BOK and its antisense transcript as demonstrated by RNAi knockdown of the HIF system. Although the antisense transcript was expressed in several human carcinoma cell lines, including choriocarcinoma-derived JEG3 cells, no antisense-regulated mechanism for BOK expression was noted. Taken together, these findings indicate that hypoxia-induced expression of BOK in placental cells is regulated via HIF and is not affected by its antisense transcript.
BOK（BCL-2 相关卵巢杀手）是凋亡促进 BCL-2 家族的成员，在人胎盘组织中高表达。BOK 过表达导致子痫前期（缺氧和氧化应激的病理性条件）中滋养细胞自噬和凋亡增加。在本研究中，我们在人 BOK 基因的外显子 1 和内含子 1 的交界处（+229 到+279）鉴定了一个 HRE（缺氧反应元件），以及一个由位于内含子 2 中的启动子驱动的反义转录本。分离的 BOK-HRE 在体外以及滋养细胞系 JEG3 中与缺氧诱导的 HIF（缺氧诱导因子）蛋白结合，并且在其自然位置以及在异源启动子前面均具有功能。作为一个反向重复序列，BOK-HRE 以两种方向起作用。BOK-HRE 的这种无定向特征通过 HIF 系统的 RNAi 敲低，促进了 BOK 和其反义转录本的缺氧调节。尽管反义转录本在几种人癌细胞系中表达，包括绒毛膜癌细胞系 JEG3 细胞，但未观察到 BOK 表达的反义调控机制。总之，这些发现表明，胎盘细胞中缺氧诱导的 BOK 表达是通过 HIF 调节的，不受其反义转录本的影响。
