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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells
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Molecular basis for the differential use of glucose and glutamine in cell proliferation as revealed by synchronized HeLa cells

机译：同步HeLa细胞揭示了葡萄糖和谷氨酰胺在细胞增殖中差异使用的分子基础

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During cell division, the activation of glycolysis is tightly regulated by the action of two ubiquitin ligases, anaphase-promoting complex/ cyclosome-Cdh1 (APC/C-Cdh1) and SKP1/CUL-1/F-box protein-p-transducin repeat-containing protein (SCF-p-TrCP), which control the transient appearance and metabolic activity of the glycolysis-promoting enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphos-phatase, isoform 3 (PFKFB3). We now demonstrate that the breakdown of PFKFB3 during S phase occurs specifically via a distinct residue (S~(273)) within the conserved recognition site for SCF-p-TrCP. Glutaminase 1 (GLS1), the first enzyme in glutaminolysis, is also targeted for destruction by APC/C-Cdh1 and, like PFKFB3, accumulates after the activity of this ubiquitin ligase decreases in mid-to-late G1. However, our results show that GLS1 differs from PFKFB3 in that its recognition by APC/C-Cdh1 requires the presence of both a Lys-Glu-Asn box (KEN box) and a destruction box (D box) rather than a KEN box alone. Furthermore, GLS1 is not a substrate for SCF-β-TrCP and is not degraded until cells progress from S to G2/M. The presence of PFKFB3 and GLS1 coincides with increases in generation of lactate and in utilization of glutamine, respectively. The contrasting post-translational regulation of PFKFB3 and GLS1, which we have verified by studies of ubiquitination and protein stability, suggests the different roles of glucose and glutamine at distinct stages in the cell cycle. Indeed, experiments in which synchronized cells were deprived of either of these substrates show that both glucose and glutamine are required for progression through the restriction point in mid-to-late G1, whereas glutamine is the only substrate essential for the progression through S phase into cell division.
机译：在细胞分裂过程中，糖酵解的激活受到两个泛素连接酶（后期促进复合物/环体-Cdh1（APC / C-Cdh1）和SKP1 / CUL-1 / F-box蛋白-p-transducin重复序列）的作用严格调控。 -含有蛋白质（SCF-p-TrCP）的蛋白质，可控制糖酵解促进酶6-磷酸果糖-2-激酶/果糖-2,6-双磷酸酶（异构体3）（PFKFB3）的瞬时出现和代谢活性。我们现在证明，PFKFB3在S期的分解是通过SCF-p-TrCP的保守识别位点内的一个独特残基（S〜（273））发生的。谷氨酰胺分解酶中的第一个酶谷氨酰胺酶1（GLS1）也被APC / C-Cdh1破坏，并且象PFKFB3一样，在泛素连接酶的活性在中晚期G1降低后累积。但是，我们的结果表明，GLS1与PFKFB3的不同之处在于，要被APC / C-Cdh1识别，GLS1需要同时存在Lys-Glu-Asn框（KEN框）和破坏框（D框），而不是单独使用KEN框。此外，GLS1不是SCF-β-TrCP的底物，并且直到细胞从S前进到G2 / M才被降解。 PFKFB3和GLS1的存在分别与乳酸生成和谷氨酰胺利用的增加相吻合。我们通过泛素化和蛋白质稳定性的研究证实了相反的PFKFB3和GLS1的翻译后调控，表明葡萄糖和谷氨酰胺在细胞周期不同阶段的不同作用。实际上，从同步细胞中剥夺了任何一种底物的实验表明，葡萄糖和谷氨酰胺都需要在中晚期G1内通过限制点而发展，而谷氨酰胺是从S期发展到S期所必需的唯一底物细胞分裂。

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    Sergio L. Colombo; Miriam Palacios-Callender; Nanci Frakich; Saul Carcamo; Istvan Kovacs; Slavica Tudzarova; Salvador Moncada;

  • 作者单位

    Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;

    Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;

    Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;

    Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;

    Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;

    Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;

    Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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