Regulation of cell proliferation ancl apoptcsis by the nansaiption factois Bach1 and Bach2

一些证据表明，基因表达不仅受转录因子和DNA之间的相互作用的调节，而且还受细胞核的高级结构的调节。PML小体是细胞核中最重要的亚结构之一，参与细胞凋亡和应激反应过程中的转录调控。Bach 2是BTB-碱性区亮氨酸拉链因子家族的成员，并且抑制由12-0-十四酰基佛波醇-13-乙酸酯响应元件、Maf识别元件和抗氧化剂响应元件指导的转录活性。Bach 2在氧化应激时形成与PML小体相关的核灶，并且当在NIH 3 T3细胞和B细胞系中过表达时诱导凋亡。与PML小体相关的转录活性被PML小体周围Bach 2的募集选择性抑制。光漂白实验后的荧光恢复显示，Bach 2在核灶中显示出快速的周转。巴赫2 N ...更多信息 包括BTB结构域的末端区域对于焦点形成是必不可少的。Bach 2的SUMO化是PML小体周围蛋白质募集所必需的，Bach 1是血红素加氧酶-1和其他血红素相关基因的转录抑制因子，其中一些基因被血红素转录诱导。为了验证血红素调节Bach 1活性的假设，我们在人293 T和GMO 2063细胞中表达了野生型和突变型Bach 1，以及或不表达其异源二聚体伴侣MafK，并检查了它们的亚细胞定位。血红素合成的抑制增强了Bach 1的核积累，而用氯化血红素处理细胞导致Bach 1的核排斥。虽然镉诱导的Bach 1的核输出信号被证明是血红素的反应，一个区域包含两个血红素结合基序被发现是血红素诱导的核排斥的关键。该区域作为血红素调节的核出口信号依赖于出口商Crm 1。这些结果扩展了血红素在蛋白质分选中的调节作用，并提示Bach 1将代谢活性转化为基因表达。通过分析野生型和Bach 1敲除的平滑肌细胞（SMC）的体外增殖，我们发现Bach 1参与了SMC的增殖。我们目前正在寻找Bach 1在SMC和成纤维细胞中的下游直接靶基因。少

Several lines of evidence suggest that gene expression is regulated not only by the interaction between transcription factors and DNA but also by the higher order architecture oft the cell nucleus. PML bodies are one of the most prominent nuclear substructures, which have been implicated in transcription regulation during apoptosis and stress responses. Bach2 is a member of the BTB-basic region leucine zipper factor family, and represses transcription activity directed by the 12-0-tetradecanoylphorbol-13-acetate response element, the Maf recognition element and the antioxidant-responsive element. Bach2 forms nuclear foci associated with PML bodies upon oxidative stress and induces apoptosis when overexpressed in NIH3T3 cells and B cell lines. Transcription activity associated with PML bodies is selectively repressed by the recruitment of Bach2 around PML bodies. Fluorescence recovery after photobleaching experiments revealed that Bach2 showed rapid turnover in the nuclear foci. Bach2 N … More terminal region including the BTB domain is essential for the focus formation. SUMOylation of Bach2 is required for the recruitment of the protein around PML bodies.Bach1 is a transcriptional repressor of heme oxygenase-1 and other heme-related genes some of which are known to be transcriptionally induced by heme. To test the hypothesis that heme regulates the activity of Bach1, we expressed wild-type and mutated versions of Bach1 together with or without its heterodimer partner MafK in human 293T and GMO2063 cells and examined their subcellular localization. Inhibition of heme synthesis enhanced the nuclear accumulation of Bach1 whereas treating cells with hemin resulted in nuclear exclusion of Bach1. While the cadmium-inducible nuclear export signal of Bach1 was dispensable for the heme response, a region containing two of the heme-binding motifs were found to be critical for the heme-induced nuclear exclusion. This region functioned as a heme-regulated nuclear export signal dependent on the exporter Crm1. These results extend the regulatory roles for heme in protein sorting, and suggest that Bach1 transduces metabolic activity into gene expression.By analyzing the proliferation of wild-type and Bach1-knockout smooth muscle cells (SMC) in vitro, we found that Bach1 is involved in the proliferation of SMC. We are currently searching for the down-stream, direct target gene of Bach1 in SMC and fibroblastic cells. Less