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首页> 外文期刊>Cell cycle >HIF-1 or HIF-2 induction is sufficient to achieve cell cycle arrest in NIH3T3 mouse fibroblasts independent from hypoxia.
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HIF-1 or HIF-2 induction is sufficient to achieve cell cycle arrest in NIH3T3 mouse fibroblasts independent from hypoxia.

机译：HIF-1或HIF-2诱导足以在独立于缺氧的NIH3T3小鼠成纤维细胞中实现细胞周期停滞。

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Hypoxia is a severe stress which induces physiological and molecular adaptations, where the latter is dominated by the Hypoxia-inducible transcription Factor (HIF). A well described response on cellular level upon exposure to hypoxia is a reversible cell cycle arrest, which probably renders the cells more resistant to the difficult environment. The individual roles of hypoxia itself and of the isoforms HIF-1alpha and HIF-2alpha in cell cycle regulation are poorly understood and discussed controversially. In order to characterize the isolated effect of both HIFalpha isoforms on the cell cycle we generated tetracycline inducible, HIF-1alpha and -2alpha expressing NIH3T3 cells. The cDNAs for HIFalpha were mutated to generate stable and active HIF under normoxia. Upon activation of both HIFalpha subunits, the total number of living cells was reduced and long-term stimulation of HIF led to complete loss of transgene expression, implicating a strong negative selection pressure. Equally, colony forming activity was reduced by activation of both HIFalpha subunits. Cell cycle analyses showed that HIF activation resulted in a prominent cell cycle arrest in G(1)-phase, similarly to the hypoxic effect. Both, HIF-1alpha and HIF-2alpha were able to induce the expression of the cyclin-dependent kinase inhibitor p27 on reporter gene and protein level. Our study shows that HIF-1 and HIF-2 can individually arrest the cell cycle independent from hypoxia. These findings have implications for the resistance of tumor cells to the environment and treatment, but also for physiological cells. Importantly, recent approaches to stabilize HIFalpha in normoxia could have deleterious effects on proliferating tissues.
机译：缺氧是一种严重的压力，会诱导生理和分子适应，其中后者主要由低氧诱导型转录因子（HIF）主导。暴露于缺氧条件下对细胞水平的良好描述的反应是可逆的细胞周期停滞，这可能使细胞对困难的环境更具抵抗力。缺氧本身以及同工型HIF-1alpha和HIF-2alpha在细胞周期调控中的个体作用还知之甚少，并引起争议。为了表征两种HIFα同工型对细胞周期的分离作用，我们生成了表达四环素的HIF-1α和-2α表达的NIH3T3细胞。将HIFalpha的cDNA突变以在常氧下生成稳定且活跃的HIF。在两个HIFalpha亚基都激活后，活细胞总数减少，长期刺激HIF导致转基因表达完全丧失，这意味着强烈的负选择压力。同样，通过激活两个HIFalpha亚基降低了菌落形成活性。细胞周期分析表明，HIF激活导致在G（1）期明显的细胞周期停滞，类似于低氧效应。 HIF-1alpha和HIF-2alpha都能在报告基因和蛋白质水平上诱导细胞周期蛋白依赖性激酶抑制剂p27的表达。我们的研究表明，HIF-1和HIF-2可以独立于缺氧而停止细胞周期。这些发现对肿瘤细胞对环境和治疗的抵抗力，以及对生理细胞的抵抗力都有影响。重要的是，在常氧中稳定HIFalpha的最新方法可能对增殖的组织产生有害影响。

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