教授Cell子刊解析缺氧诱导因子
生物通报道：活细胞中存在着一个复杂的响应机制，能帮助它们在氧含量较低的条件下存活下来。缺氧诱导因子HIF在这一过程中起到了关键性的作用。目前人们普遍认为，HIF-1 和HIF-2是转录激活蛋白，而HIF-3负责抑制HIF-1/2α的活性。但中国海洋大学的科学家们在Cell旗下的Cell Reports杂志上发表文章指出，事实并非如此。
包括炎症和癌症在内的多种疾病，都与细胞的缺氧条件息息相关。近年来，细胞对缺氧条件的应答已经成为了一个重要的研究课题。（推荐阅读：JBC详解低氧下的细胞行为）
中国海洋大学海洋药物教育部重点实验室的研究团队，在段存明教授的领导下，对斑马鱼的缺氧诱导因子进行了深入研究。他们发现，在常氧条件下Hif-3α会被降解，而缺氧能增加Hif-3α的稳定性。研究显示斑马鱼的Hif-3α具有很强的反式激活活性，能够在缺氧条件下与目标基因的启动子结合，提高这些基因的表达水平。
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随后，研究人员通过转录组分析和染色质免疫沉淀，鉴定了受到Hif-3或Hif-1调控的基因。他们发现Hif-3的反式激活活性是进化保守的，人类HIF-3α-1和斑马鱼HIF-3α-9具有类似的活性，调控着类似的目的基因。
文章总结道，Hif-3是氧含量依赖性的转录因子，负责激活细胞对缺氧条件的应答。Hif-3α不仅介导了缺氧诱导的生长和发育迟缓，还具有不依赖于缺氧条件的其他活性。
原文摘要：
Hypoxia-Inducible Factor 3 Is an Oxygen-Dependent Transcription Activator and Regulates a Distinct Transcriptional Response to Hypoxia
Hypoxia-inducible factors (HIFs) play key roles in the cellular response to hypoxia. It is widely accepted that whereas HIF-1 and HIF-2 function as transcriptional activators, HIF-3 inhibits HIF-1/2α action. Contrary to this idea, we show that zebrafish Hif-3α has strong transactivation activity. Hif-3α is degraded under normoxia. Mutation of P393, P493, and L503 inhibits this oxygen-dependent degradation. Transcriptomics and chromatin immunoprecipitation analyses identify genes that are regulated by Hif-3α, Hif-1α, or both. Under hypoxia or when overexpressed, Hif-3α binds to its target gene promoters and upregulates their expression. Dominant-negative inhibition and knockdown of Hif-3α abolish hypoxia-induced Hif-3α-promoter binding and gene expression. Hif-3α not only mediates hypoxia-induced growth and developmental retardation but also possesses hypoxia-independent activities. Importantly, transactivation activity is conserved and human HIF-3α upregulates similar genes in human cells. These findings suggest that Hif-3 is an oxygen-dependent transcription factor and activates a distinct transcriptional response to hypoxia.
