Giaccia A J, Auger E A, Koong A, Terris D J, Minchinton A I, Hahn G M, Brown J M
Department of Radiation Oncology, Stanford University, CA 94305.
Int J Radiat Oncol Biol Phys. 1992;23(4):891-7. doi: 10.1016/0360-3016(92)90667-7.
Cells exposed to hypoxia increase their synthesis of a specific set of proteins called oxygen regulated proteins. Recently, three of these proteins have been identified as hemoxygenase, Glucose Regulated Protein 78 kilodaltons and Glucose Regulated Protein 94 kilodaltons. In contrast, reoxygenation from hypoxic conditions increases the synthesis of the heat shock proteins. Although the molecular signals required for regulation of both sets of proteins by hypoxia and reoxygenation are still under investigation, it is known that their expression is regulated at the transcriptional level. This finding suggests that these stresses work either singularly or together to control the activation of nuclear transcription factors which bind distinct regulatory sequences in the promoter region of these genes. One possible nuclear transcription factor which could act as a transcriptional regulator for both hypoxia and reoxygenation gene transcription is the heat shock transcription factor. In this report, we focused on the kinetics of HSF activation by hypoxia in normal and tumor cell lines of murine and human origins. In cell culture, both the normal diploid cell line AG1522 and the tumor cell line JSQ-3 possess the same kinetics of HSF activation (binding to the heat shock element) by hypoxia, with maximal induction at or after 3 hr. We have also shown that the activation of HSF occurs in the SCCVII tumor in vivo without clamping, but not in SCCVII cells grown in monolayers. When SCCVII tumors are dissociated and allowed to reoxygenate in cell culture, HSF binding decreased in 5 hr, and was undetectable after 18 hr. Furthermore, one human tumor biopsy tested for the presence of hypoxia by both the pO2 histograph (Eppendorf, Germany) and HSF binding showed good agreement for both techniques. These results suggest that HSF binding may be a useful marker for monitoring the tumor hypoxia.
暴露于低氧环境下的细胞会增加一组特定蛋白质（称为氧调节蛋白）的合成。最近，其中三种蛋白质已被鉴定为血红素加氧酶、78 千道尔顿葡萄糖调节蛋白和 94 千道尔顿葡萄糖调节蛋白。相比之下，从低氧状态复氧会增加热休克蛋白的合成。尽管低氧和复氧调节这两组蛋白质所需的分子信号仍在研究中，但已知它们的表达在转录水平受到调控。这一发现表明，这些应激单独或共同作用，以控制与这些基因启动子区域中不同调控序列结合的核转录因子的激活。一种可能作为低氧和复氧基因转录的转录调节因子的核转录因子是热休克转录因子。在本报告中，我们重点研究了低氧对源自小鼠和人类的正常及肿瘤细胞系中热休克转录因子激活的动力学。在细胞培养中，正常二倍体细胞系 AG1522 和肿瘤细胞系 JSQ - 3 在低氧条件下具有相同的热休克转录因子激活动力学（与热休克元件结合），在 3 小时或 3 小时后诱导达到最大值。我们还表明，热休克转录因子的激活在体内的 SCCVII 肿瘤中无钳夹时发生，但在单层培养的 SCCVII 细胞中不发生。当 SCCVII 肿瘤解离并在细胞培养中复氧时，热休克转录因子结合在 5 小时内减少，18 小时后无法检测到。此外，通过 pO2 组织图谱仪（德国 Eppendorf）和热休克转录因子结合对一份人类肿瘤活检样本进行低氧检测，两种技术结果吻合良好。这些结果表明，热休克转录因子结合可能是监测肿瘤低氧的有用标志物。
