Failure to prolyl hydroxylate hypoxia-inducible factor α phenocopies VHL inactivation in vivo
Failure to prolyl hydroxylate hypoxia-inducible factor α phenocopies VHL inactivation in vivo
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DOI：
10.1038/sj.emboj.7601300
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发表时间：
2006-10-04
期刊：
影响因子：
11.4
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
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作者：
Kim, William Y.;Safran, Michal;Kaelin, William G., Jr.
Von Hippel-Lindau肿瘤抑制基因产物(PVHL)具有许多功能，包括靶向异源二聚体转录因子HIF(缺氧诱导因子)的α亚基进行破坏。PVHL与HIFα的结合需要HIFA在两个脯氨酸残基中的一个上羟基化。我们将不能在这些位点上羟化的HIF1α和HIF2α变体引入普遍表达的rosa26基因座，以及使它们的表达依赖于Cre的Lox-Stop-Lox盒。HIF2A变异体在皮肤和肝脏中的表达引起的变化与pVHL在这些器官中丢失时所见的变化高度相似。然而，HIF1a和HIF2A变体在肝脏中的双重表达比单独表达HIF2A变体更能反映pVHL失活后的变化。此外，基因表达谱证实，肝脏中受HIF1a和HIF2a调控的基因是重叠的，但不相同。因此，pVHL失活在皮肤和肝脏引起的病理改变很大程度上是由于HIF靶基因的调控失调。
Many functions have been assigned to the von Hippel-Lindau tumor suppressor gene product (pVHL), including targeting the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction. The binding of pVHL to HIF alpha requires that HIFa be hydroxylated on one of two prolyl residues. We introduced HIF1 alpha and HIF2 alpha variants that cannot be hydroxylated on these sites into the ubiquitously expressed ROSA26 locus along with a Lox-stop-Lox cassette that renders their expression Cre-dependent. Expression of the HIF2a variant in the skin and liver induced changes that were highly similar to those seen when pVHL is lost in these organs. Dual expression of the HIF1a and HIF2a variants in liver, however, more closely phenocopied the changes seen after pVHL inactivation than did the HIF2a variant alone. Moreover, gene expression profiling confirmed that the genes regulated by HIF1a and HIF2a in the liver are overlapping but non- identical. Therefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to dysregulation of HIF target genes.