The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.
The tumor suppressor folliculin inhibits lactate dehydrogenase A and regulates the Warburg effect.
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DOI：
10.1038/s41594-021-00633-2
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发表时间：
2021-08
影响因子：
16.8
通讯作者：
Mollapour, Mehdi
中科院分区：
文献类型：
--
作者：
Woodford, Mark R.;Baker-Williams, Alexander J.;Sager, Rebecca A.;Backe, Sarah J.;Blanden, Adam R.;Hashmi, Fiza;Kancherla, Priyanka;Gori, Alessandro;Loiselle, David R.;Castelli, Matteo;Serapian, Stefano A.;Colombo, Giorgio;Haystead, Timothy A.;Jensen, Sandra M.;Stetler-Stevenson, William G.;Loh, Stewart N.;Schmidt, Laura S.;Linehan, W. Marston;Bah, Alaji;Bourboulia, Dimitra;Bratslavsky, Gennady;Mollapour, Mehdi
癌细胞中的有氧糖酵解，也称为“瓦伯格效应”，是由乳酸脱氢酶 A (LDHA) 的过度活跃驱动的。 LDHA 被认为是一种底物调节酶，但尚不清楚是否有专门的细胞内蛋白也调节其活性。在这里，我们将人肿瘤抑制滤泡蛋白 (FLCN) 确定为 LDHA 的结合伴侣和非竞争性抑制剂。 FLCN 氨基末端内的柔性环控制 LDHA 活性位点环的运动，严格调节其酶活性，从而调节正常细胞的代谢稳态。经历 Warburg 效应的癌细胞显示 FLCN 与 LDHA 解离。用源自 FLCN 环区域的十肽处理这些细胞会导致细胞死亡。我们的数据表明癌细胞的糖酵解转变是 FLCN 失活或从 LDHA 解离的结果。总之，FLCN 介导的 LDHA 抑制为糖酵解的调节提供了新的范例。
Aerobic glycolysis in cancer cells, also known as the ‘Warburg effect’, is driven by hyperactivity of lactate dehydrogenase A (LDHA). LDHA is thought to be a substrate-regulated enzyme, but it is unclear whether a dedicated intracellular protein also regulates its activity. Here, we identify the human tumor suppressor folliculin (FLCN) as a binding partner and uncompetitive inhibitor of LDHA. A flexible loop within the amino terminus of FLCN controls movement of the LDHA active-site loop, tightly regulating its enzyme activity and, consequently, metabolic homeostasis in normal cells. Cancer cells that experience the Warburg effect show FLCN dissociation from LDHA. Treatment of these cells with a decapeptide derived from the FLCN loop region causes cell death. Our data suggest that the glycolytic shift of cancer cells is the result of FLCN inactivation or dissociation from LDHA. Together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
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影响因子：
14.9
作者：
Cer RZ;Mudunuri U;Stephens R;Lebeda FJ
通讯作者：
Lebeda FJ
影响因子：
56.9
作者：
Lawrence, Rosalie E.;Fromm, Simon A.;Zoncu, Roberto
通讯作者：
Zoncu, Roberto
影响因子：
8.8
作者：
通讯作者：
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DOI：
10.1073/pnas.0914433107
发表时间：
2010-02-02
影响因子：
11.1
作者：
Le, Anne;Cooper, Charles R.;Dang, Chi V.
通讯作者：
Dang, Chi V.
影响因子：
5.8
作者：
Nookala RK;Langemeyer L;Pacitto A;Ochoa-Montaño B;Donaldson JC;Blaszczyk BK;Chirgadze DY;Barr FA;Bazan JF;Blundell TL
通讯作者：
Blundell TL