Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1α (HIF-1α):: Role of cytoplasmic trapping of HIF-2α
Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1α (HIF-1α):: Role of cytoplasmic trapping of HIF-2α
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DOI：
10.1128/mcb.23.14.4959-4971.2003
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发表时间：
2003-07-01
影响因子：
5.3
通讯作者：
Johnson, RS
中科院分区：
文献类型：
--
作者：
Park, SK;Dadak, AM;Johnson, RS
低氧诱导因子let（HIF-1 α）和2 α（HIF-2 α）具有广泛的结构同源性，并且已被鉴定为负责响应低氧的基因表达的关键转录因子。它们不仅在正常发育中起关键作用，而且在肿瘤进展中也起关键作用。在这里，我们报告的差异调节蛋白质表达和HIF-1 α和-2 α的转录活性缺氧在永生化小鼠胚胎成纤维细胞（MEFs）。我们展示了氧依赖蛋白。降解仅限于HIF-1 α，因为在MEFs中检测到HIF-2 α蛋白，而与氧合无关，并且主要定位于细胞质。内源性HIF-2 α在缺氧条件下保持转录活性;然而，异位过表达的HIF-2 α易位到细胞核中，可以刺激缺氧诱导基因的表达。我们发现，抑制HIF-1的因子可以选择性地抑制HIF-1 α的转录活性，但对HIF-2 α介导的MEFs转录没有影响。我们认为HIF-2 α不是HIF-1 α的冗余转录因子。低氧诱导基因表达，并显示存在细胞类型特异性调节剂的证据，其能够响应低氧应激选择性激活HIF-1 α而非HIF-2 α。
The hypoxia-inducible factors let (HIF-1alpha) and 2alpha (HIF-2alpha) have extensive structural homology and have been identified as key transcription factors responsible for gene expression in response to hypoxia. They play critical roles not only in normal development, but also in tumor progression. Here we report on the differential regulation of protein expression and transcriptional activity of HIF-1alpha and -2alpha by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein. degradation is restricted to HIF-1alpha, as HIF-2alpha protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2alpha remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2alpha translocated into the nucleus and could stimulate expression of hypoxia-inducible genes. We show that the factor inhibiting HIF-1 can selectively inhibit the transcriptional activity of HIF-1alpha but has no effect on HIF-2alpha-mediated transcription in MEFs. We propose that HIF-2alpha is not a redundant transcription factor of HIF-1alpha for. hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1alpha but not HIF-2alpha in response to low-oxygen stress.