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首页> 外文期刊>Molecular and Cellular Biology >Hypoxia-Inducible Factor 1 Is Activated by Dysregulated Cyclin E during Mammary Epithelial Morphogenesis
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Hypoxia-Inducible Factor 1 Is Activated by Dysregulated Cyclin E during Mammary Epithelial Morphogenesis

机译：乳腺上皮形态发生过程中细胞周期蛋白E失调激活了缺氧诱导因子1。

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Increased cyclin E expression has been identified in human tumors of diverse histologies, and in studies of primary breast cancers, high cyclin E is associated with poor prognosis. We have studied dysregulated cyclin E in epithelial tissues using organotypic cultures of human mammary epithelial cells and a murine model. We unexpectedly discovered that dysregulated cyclin E impairs normal acinar morphogenesis in vitro, and this is associated with the induction of p21Cip1, p27Kip1, and cellular senescence. Cyclin E-induced morphogenesis arrest is dependent upon hypoxia-inducible factor 1α (HIF-1α), which itself is induced by high cyclin E both in cultured mammary acini and in mammary epithelial tissues in a mouse model of deregulated cyclin E expression. We next determined that E2F activity directly regulates and is required for induction of HIF1A by cyclin E. Additionally, we found that cyclin E deregulation in mammary acini decreases, in an E2F-independent manner, expression of the EGLN1 prolyl hydroxylase that regulates HIF-1α degradation within the VHL ubiquitin ligase pathway. Together, our findings reveal a direct link between cyclin E and HIF-1 activities in mammary epithelial cells and implicate HIF-1 as a mediator of proliferation-independent phenotypes associated with high cyclin E expression in some human breast cancers.
机译：已经在各种组织学的人类肿瘤中发现了细胞周期蛋白E表达的增加，在原发性乳腺癌的研究中，细胞周期蛋白E高与预后差有关。我们已经使用人乳腺上皮细胞的有机型培养和小鼠模型研究了上皮组织中细胞周期蛋白E失调。我们意外地发现，细胞周期蛋白E失调会在体外 损害正常的腺泡形态发生，这与p21 Cip1 ，p27 Kip1 和细胞衰老。细胞周期蛋白E诱导的形态发生停滞取决于缺氧诱导因子1α（HIF-1α），低氧诱导因子1α（HIF-1α）本身是由高细胞周期蛋白E诱导的，在培养的乳腺腺泡和乳腺上皮组织中，细胞周期蛋白E表达失调。接下来，我们确定E2F活性直接调节并且是细胞周期蛋白E诱导 HIF1A 所必需的。此外，我们发现，乳腺腺泡蛋白中的细胞周期蛋白E失调以E2F无关的方式降低了EGLN1的表达脯氨酰羟化酶，可调节VHL泛素连接酶途径中的HIF-1α降解。在一起，我们的发现揭示了在乳腺上皮细胞中细胞周期蛋白E和HIF-1活性之间存在直接联系，并暗示HIF-1作为某些人类乳腺癌中与细胞周期蛋白E高表达相关的增殖依赖性表型的介质。

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