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首页> 外文期刊>Molecular and Cellular Biology >Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice
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Inactivation of the Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Suppresses von Hippel-Lindau Disease-Associated Vascular Tumors in Mice

机译：芳烃受体核转运蛋白（Arnt）的失活抑制了von Hippel-Lindau病相关的小鼠血管肿瘤

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Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1α (Hif-1α) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1α did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.
机译：在 VHL 肿瘤抑制基因中发生种系突变的患者易患多种组织内高度血管化的肿瘤。 pVHL的丧失导致转录因子HIF-1和HIF-2的组成性激活，其对VHL表型发病机理的相对贡献尚待确定。为了检查HIF在von Hippel-Lindau（VHL）相关血管肿瘤发生中的作用，我们利用Cre- loxP 介导的重组来灭活缺氧诱导因子-1α（ Hif-海绵状肝血管瘤和红细胞增多症的VHL小鼠模型中的1 α）和芳基烃受体核转运子（ Arnt ）基因。删除 Hif-1 α不会影响血管肿瘤和红细胞增多症的发生，也不会抑制血管内皮生长因子（ Vegf ）和促红细胞生成素（< em> Epo ）。相比之下，磷酸甘油激酶（ Pgk ）的表达显着降低，为不同Hif转录因子之间靶基因依赖的功能冗余提供了证据。 Arnt 的失活完全抑制了血管瘤，红细胞增多症和Hif诱导的基因表达的发展。在这里，我们从基因上证明肝脏中与VHL相关的血管肿瘤的发展取决于功能性ARNT。此外，我们提供的证据表明，单个HIF转录因子可能在特定VHL疾病表现的发展中起不同的作用。

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