Löfstedt Tobias, Fredlund Erik, Noguera Rosa, Navarro Samuel, Holmquist-Mengelbier Linda, Beckman Siv, Påhlman Sven, Axelson Håkan
Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, University Hospital MAS, Entrance 78, S-20502 Malmö, Sweden.
Exp Cell Res. 2009 Jul 1;315(11):1924-36. doi: 10.1016/j.yexcr.2009.02.015. Epub 2009 Feb 27.
Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and breast cancer cells. HIF-binding and transactivation were detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.
适应低氧条件对于维持包括实体瘤在内的耗氧多细胞组织中的稳态和生存能力至关重要。这些过程的核心是缺氧诱导转录因子HIF-1和HIF-2，它们控制着参与例如葡萄糖代谢和新血管形成的基因。肿瘤缺氧和HIF表达也与去分化表型和侵袭性增加有关。在本报告中，我们表明MAX相互作用因子1（MXI1）基因在神经母细胞瘤和乳腺癌细胞中受HIF蛋白直接调控。在MXI1-0启动子附近的MXI1基因调控序列内检测到HIF结合和反式激活，导致交替的MXI1-0异构体快速诱导，随后是MXI1-0和MXI1异构体的长期诱导。重要的是，在缺氧条件下敲低MXI1对MYC/MYCN活性的影响有限，这一观察结果可能与两种MXI1异构体的不同功能属性有关。
