HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis:: Novel mechanism for HIF-1-mediated vascular endothelial growth factor expression
HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis:: Novel mechanism for HIF-1-mediated vascular endothelial growth factor expression
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DOI：
10.1128/mcb.21.12.3995-4004.2001
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发表时间：
2001-06-01
影响因子：
5.3
通讯作者：
Semenza, GL
中科院分区：
文献类型：
--
作者：
Laughner, E;Taghavi, P;Semenza, GL
缺氧诱导因子1 （Hypoxia inducible factor 1, HIF-1）是由HIF-1 α和HIF-1 β亚基组成的转录激活因子。已知的HIF-1靶点有几十个，包括编码血管内皮生长因子（VEGF）的基因。在缺氧条件下，HIF-1 α。由于泛素化和降解减少，表达增加。肿瘤抑制因子VHL （von Hippel-Lindau蛋白）和p53靶向HIF-1 α泛素化，因此它们在肿瘤细胞中的失活延长了HIF-1 α的半衰期。前列腺癌细胞中磷脂酰肌醇3-激酶（PI3K）和AKT的增加或PTEN活性的降低也会增加HIF-1 α的表达，其机制尚不明确。在乳腺癌中，HER2（也称为新）受体酪氨酸激酶活性的增加与肿瘤分级增加、化疗耐药和患者生存率降低有关。HER2也被认为是VEGF表达的诱导因子。在这里，我们证明了HER2信号在小鼠3T3细胞中过度表达或heregulin刺激人MCF-7乳腺癌细胞导致HIF-1 α蛋白和VEGF mRNA表达增加，这依赖于PI3K、AKT（也称为蛋白激酶B）和下游激酶FRAP （fkbp -雷帕霉素相关蛋白）的活性。与其他HIF-1表达诱导剂相比，heregulin刺激不影响HIF-1 α的半衰期。而是以雷帕霉素依赖的方式刺激HIF-1 α的合成。HIF-1 α mRNA的5'-非翻译区指导heregulin诱导的异源蛋白的表达。这些数据为heregulin-HER2信号通路诱导VEGF和肿瘤血管生成提供了分子基础，并为HIF-1 α表达调控建立了新机制。
Hypoxia inducible factor 1 (HIF-1) is a transcriptional activator composed of HIF-1 alpha and HIF-1 beta subunits. Several dozen HIF-1 targets are known, including the gene encoding vascular endothelial growth factor (VEGF). Under hypoxic conditions, HIF-1 alpha. expression increases as a result of decreased ubiquitination and degradation. The tumor suppressors VHL (von Hippel-Lindau protein) and p53 target HIF-1 alpha for ubiquitination such that their inactivation in tumor cells increases the half-life of HIF-1 alpha. Increased phosphatidylinositol 3-kinase (PI3K) and AKT or decreased PTEN activity in prostate cancer cells also increases HIF-1 alpha expression by an undefined mechanism. In breast cancer, increased activity of the HER2 (also known as neu) receptor tyrosine kinase is associated with increased tumor grade, chemotherapy resistance, and decreased patient survival. HER2 has also been implicated as an inducer of VEGF expression. Here we demonstrate that HER2 signaling induced by overexpression in mouse 3T3 cells or heregulin stimulation of human MCF-7 breast cancer cells results in increased HIF-1 alpha protein and VEGF mRNA expression that is dependent upon activity of PI3K, AKT (also known as protein kinase B), and the downstream kinase FRAP (FKBP-rapamycin-associated protein). In contrast to other inducers of HIF-1 expression, heregulin stimulation does not affect the half-life of HIF-1 alpha. but instead stimulates HIF-1 alpha synthesis in a rapamycin-dependent manner. The 5'-untranslated region of HIF-1 alpha mRNA directs heregulin-inducible expression of a heterologous protein. These data provide a molecular basis for VEGF induction and tumor angiogenesis by heregulin-HER2 signaling and establish a novel mechanism for the regulation of HIF-1 alpha expression.