Skp2 dictates cell cycle-dependent metabolic oscillation between glycolysis and TCA cycle  

作　　者：Jing Liu Yunhua Peng Le Shi Lixin Wan Hiroyuki Inuzuka Jiangang Long Jianping Guo Jinfang Zhang Min Yuan Shuangxi Zhang Xun Wang Jing Gao Xiangpeng Dai Shozo Furumoto Lijun Jia Pier Paolo Pandolfic John M.Asara William G.Kaelin Jr. Jjankang Liu Wenyi Wei 

机构地区：[1]Department of Pathology,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA 02215,USA [2]Center for Mitochondrial Biology and Medicine,The Key Lab oratory of Biomedical Information Engineering of Ministry of Education,School of Life Science and Technology and Frontier Institute of Science and Technology,Xi'an Jiaotong University,Xi'an,Shaanxi 710049,China [3]Department of Molecular Oncology,H.Lee Moffitt Cancer Center and Research Institute,Tampa,FL 33612,USA [4]lnstitute of Precision Medicine,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510275,China [5]Medical Research Institute,School of Medicine,Wuhan University,Wuhan,Hubei 430071,China [6]Cancer Research Institute,Beth Israel Deaconess Cancer Center,Department of Medicine and Pathology,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA 02215,USA [7]Children's Medical Center Research Institute,University of Texas Southwestern Medical Center,Dallas,TX 75390,USA [8]Division of Radiopharmaceutical Chemistry,Cyclotron and Radioisotope Center,Tohoku University,Sendai 980-857&Japan [9]Cancer Institute,Longhua Hospital,Shanghai University of Traditional Chinese Medicine,Shanghai 200032,China [10]Division of Signal Transduction,Beth Israel Deaconess Medical Center and Department of Medicine,Harvard Medical School,Boston,MA 02215,USA [11]Howard Hughes Medical Institute,Chevy Chase,MD,USA [12]Department of Medical Oncology,Dana-Farber Cancer Institute,Harvard Medical School,Boston,MA,USA

出　　处：《Cell Research》2021年第1期80-93,共14页细胞研究（英文版）

基　　金：supported in part by the NIH grants(CA229307 and CA200573 to W.W.;CAI 83914 to L.W.;R01CA068490,P50CA101942 and R35CA210068 to W.G.K.);the National Basic Research Program of China(2015CB553602 to J.K.L.;2015CB856302 to J.G.L.);the National Natural Science Foundation of China(91649106,31570777,31770917 and 31700684 to J.K.L.;81802787 to Y.P.);Fundamental Research Funds for the Central Universities(08143008 and 08143101 to J.K.L.;zrzd2017013 to J.G.L.);American Cancer Society(to H.I.).

摘　　要：Whether glucose is predomi nantly metabolized via oxidative phosphorylati on or glycolysis differs between quiesce nt versus proliferating cells,iincluding tumor cells.However,how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive.Here,we report that mammalian cells predominantly utilize the tricarboxylic acid(TCA)cycle in G1 phase,but prefer glycolysis in S phase.Mechanistically,coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2,key TCA cycle enzymes,in a Skp2-dependent manner.As such,depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance,leading to reduced glycolysis in S phase.Furthermore,elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis.Therefore,our study reveals a mechanistic link between two cancer hallmarks,aberrant cell cycle and addiction to glycolysis,and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.

关 键 词：SKP2 METABOLISM GLYCOLYSIS 

分 类 号：Q2[生物学—细胞生物学]