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首页> 外文期刊>Journal of Cellular Physiology >Activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway.
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Activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway.

机译：激活HIF-1alpha指数增长细胞通过缺氧刺激无关一种蛋白激酶/ mTOR通路。

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摘要

Accumulation of HIF-1alpha during normoxic conditions at high cell density has previously been shown to occur and can be used to stabilize HIF-1alpha protein in the absence of a specific anaerobic chamber. However, the impact and origin of this pool of HIF-1alpha, obtained under normoxia, has been underestimated. In this study, we have systematically compared the related pools of HIF-1alpha stabilized in normoxia by high cell density to those obtained at low density in hypoxia. At first glance, these two stimuli appear to have similar outcomes: HIF-1alpha stabilization and induction of HIF-1-dependent genes. However, upon careful analysis, we observed that molecular mechanisms involved are different. We clearly demonstrate that density-dependant HIF-1alpha accumulation during normoxia is due to the cells high consumption of oxygen, as demonstrated by using a respiration inhibitor (oligomycin) and respiratory-defective mutant cells (GSK3). Finally and most importantly, our data indicate that a decrease in AKT activity followed by a total decrease in p70(S6K) phosphorylation reflecting a decrease in mTOR activity occurs during high oxygen consumption, resulting from high cell density. In contrast, hypoxia, even at severe low O(2) levels, only slightly impacts upon the mTOR pathway under low cell density conditions. Thus, activation of HIF-1alpha in exponentially growing cells via hypoxic stimulation is independent of the Akt/mTOR pathway whereas HIF-1alpha activation obtained in high confluency is totally dependent on mTOR pathway as rapamycin totally impaired (i) HIF-1alpha stabilization and (ii) mRNA levels of CA9 and BNIP3, two HIF-target genes.
机译：在常氧HIF-1alpha积累条件高细胞密度被证明发生,可用于稳定HIF-1alpha没有一个特定的蛋白质厌氧室。HIF-1alpha池,下获得的normoxia,被低估了。我们有系统地比较了相关的池在normoxia HIF-1alpha稳定高细胞获得低密度的密度缺氧。似乎也有类似的结果:HIF-1alpha稳定和HIF-1-dependent感应基因。观察到的分子机制不同。density-dependant HIF-1alpha积累在normoxia是由于细胞的高消费使用呼吸氧气,证明了抑制剂(寡霉素)和respiratory-defective突变细胞(GSK3)。重要的是,我们的数据表明下降一种蛋白激酶活动总共减少紧随其后p70 (S6K)磷酸化反射降低mTOR活动发生在高氧消费,造成高细胞密度。相反,缺氧,甚至在严重低O (2)mTOR水平,仅略有影响低细胞密度条件下路径。激活HIF-1alpha指数增长细胞通过缺氧刺激无关一种蛋白激酶/ mTOR通路而HIF-1alpha在高confluency完全激活了雷帕霉素完全依赖mTOR通路受损(i) HIF-1alpha稳定和(2)两个HIF-target CA9和BNIP3的mRNA水平基因。

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