HIF1α and HIF2α exert distinct nutrient preferences in renal cells.
HIF1α and HIF2α exert distinct nutrient preferences in renal cells.
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DOI：
10.1371/journal.pone.0098705
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Rathmell WK
中科院分区：
文献类型：
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作者：
Arreola A;Cowey CL;Coloff JL;Rathmell JC;Rathmell WK
低氧诱导因子(HIF1α和HIF2α)在肾透明细胞癌的细胞生长和代谢编程中起关键作用。这些因素离散性改变细胞代谢活动的关系在很大程度上已经在癌细胞中得到了描述，或者在低氧条件下，其他混杂因素无疑会相互竞争。这些转录因子及其在早期促进癌症代谢表型中的特定作用在癌前细胞中知之甚少。我们对来自基因工程新生小鼠的SV40转化的原代肾上皮细胞进行了分析，这些细胞表达稳定的HIF1α或HIF2α转基因。我们检查了与每个基因相关的代谢谱。尽管细胞增殖相似，但每种类型细胞的代谢谱明显不同，并与影响代谢信号成分的因素的基因表达变化相关。HIF1α在完全培养时促进高水平的糖酵解并增加氧化磷酸化，但在单一碳源供应时氧化磷酸化受到抑制。相反，Hif2α支持在全培养液或单一葡萄糖碳源中的氧化磷酸化，但这些细胞对谷氨酰胺营养源没有反应。这一发现与HIF2GLUL的特异性诱导有关，通过限制谷氨酸库有效地减少了谷氨酰胺的利用，并且GLUL的敲除允许这些细胞在谷氨酰胺介质中进行氧化磷酸化。HIF1α和HIF2α支持高度不同的肾上皮细胞代谢表型。这些因素的表达最终改变了营养资源的利用和在设置完全或限制营养的情况下的能量产生策略。
Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells. We undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene. Although the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media. HIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients.
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DOI：
10.1073/pnas.93.20.10595
发表时间：
1996-10-01
影响因子：
11.1
作者：
Iliopoulos, O;Levy, AP;Goldberg, MA
通讯作者：
Goldberg, MA
影响因子：
4.8
作者：
Cockman, ME;Masson, N;Maxwell, PH
通讯作者：
Maxwell, PH
影响因子：
11.4
作者：
Kim, William Y.;Safran, Michal;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.
影响因子：
11.2
作者：
Kurban, G;Hudon, V;Pause, A
通讯作者：
Pause, A
影响因子：
64.8
作者：
通讯作者：
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