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吕志民

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吕志民
教授,博士生导师

研究领域:
• 肿瘤代谢

• 肿瘤发生与发展

吕志民教授三个原创性里程碑发现,深刻影响了业界对肿瘤代谢的认识, 同时也对开拓新的肿瘤诊治方法提供了创新理论支持:

1.国际上首次阐明生长因子受体促进 Warburg 效应的分子机制
Warburg 效应是近百年前由德国诺贝尔奖获得者 Warburg 发现的肿瘤代谢 特征; 即肿瘤细胞即使在有氧条件下依然依赖糖酵解供给能量, 而抑制线粒 体能量代谢的现象。Warburg 效应是临床广泛使用的 PET 检查的理论基础, 但其分子机制一直不明确。吕教授发现, 生长因子受体激活诱导糖酵解酶丙 酮酸激酶 M2(PKM2)转入细胞核内,结合并激活 beta-catenin (Nature, 2011); 磷酸化组蛋白 H3(Cell,2012) (被 Science Signaling 评选为 2012 年信号转导 领域的重大突破); 上调糖酵解基因表达并增强葡萄糖摄取和乳酸产生 (Nature Cell Biology, 2012; Molecular Cell, 2012)。另外,首次报导糖酵解 酶磷酸甘油酸激酶(PGK1)转入线粒体,磷酸化并激活丙酮酸脱氢酶激酶 1(PDHK1),进而抑制线粒体丙酮酸代谢,从而促进 Warburg 效应(Molecular Cell, 2016)。因此, 吕教授揭示该效应是通过细胞核内 PKM2 和线粒体内 PGK1 调节的。
2.国际上首次发现多种重要的代谢酶同时具有蛋白激酶活性
除磷酸化组蛋白外, PKM2 还磷酸化纺锤体组装蛋白 Bub3 以调节细胞分裂 中期的染色体分离, 磷酸化肌球蛋白轻链 2 以促进胞质分裂(Molecular Cell, 2014)。首次报导肝癌细胞剪接果糖激酶 KHK 基因以表达 KHK-A,其作为 蛋白激酶磷酸化并激活磷酸核糖的焦磷酸合成酶 1(PRPS1)以促进核酸合 成、肝癌形成(Nature Cell Biology, 2016)。另外, KHK-A 磷酸化 p62,激活 Nrf2 促进肿瘤细胞抗氧化反应(Science Advances, 2019)。除了磷酸化 PDHK1 以调节线粒体功能, PGK1 磷酸化 Beclin1 调节自噬(Molecular Cell, 2017)。因此,代谢酶具有蛋白激酶功能的发现为肿瘤诊疗提供了重要靶点。
3.国际上率先证实多种代谢酶和代谢产物在肿瘤细胞活动调控中具有重要的非代谢功能, 并因此发现多个肿瘤代谢新靶点
代谢酶和代谢物调节基因表达、有丝分裂、胞质分裂、核酸合成和自噬(Nature Reviews Molecular Cell Biology, 2018)。另外发现(a) 延胡索酸酶调节 DNA 修复(Nature Cell Biology, 2015); (b) 核乙酰辅酶 A 合成酶 2 (ACSS2)在启 动子区域产生乙酰辅酶 A, 诱导溶酶体生物合成和自噬基因的表达 (Molecular Cell, 2017); (c) α-KGDH 关联的 Gcn5 作为组蛋白 H3 琥珀酰转 移酶以调节基因表达(Nature, 2017); (d) 磷酸果糖激酶 1(PFKP)促进 PI3K 激活(Molecular Cell, 2018)。因此, 其科研成果改变了业界对肿瘤代谢的传统认知。

教育背景:
1998 美国纽约市立大学 分子、细胞及发育生物学专业 博士
1986 泰山医学院 临床医学专业 学士

研究工作经历:
2019—至今  浙江大学转化医学研究院 院长
2015—2018 美国德克萨斯大学MD安德森癌症中心Ruby E. Rutherford杰出教授
2013—2018 德克萨斯大学安德森癌症中心神经肿瘤学 教授(终身教职)
2009—2013 德克萨斯大学安德森癌症中心神经肿瘤学 副教授(终身教职)
2003—2009 德克萨斯大学安德森癌症中心神经肿瘤学 助理教授
1999—2003  SALK生物学研究所分子细胞肿瘤学 研究助理/博士后
1993—1999 纽约市立大学研究生院分子细胞肿瘤学 研究助理
1986—1993 青岛医院肿瘤内科 医生

荣誉及奖项:
2019 浙江大学王宽诚杰出讲席教授
2018 美国国家艺术与科学院院士提名
2017 美国科学促进会(American Association for the Advancement of Science )会士
2016 美国德克萨斯大学MD安德森癌症中心Dallas/Fort Worth传奇人物基础研究成就奖
2015 美国德克萨斯大学科学技术获得和保留(STARs)奖
2013 美国德克萨斯大学MD安德森癌症中心Potu N. Rao基础科学卓越奖
2012 美国James S. McDonnell基金会学者奖
2011 美国德克萨斯大学MD安德森癌症中心Faculty学者奖
2009 美国癌症协会研究学者奖
2008 美国Peter Steck青年研究者奖
2005 中国科学院王宽诚基金会奖
2000 美国加州乳腺癌研究计划博士后奖学金
1999 美国Salk先锋基金奖学金
1997 美国纽约城市大学亨特学院生命科学 Beatrice Goldstein Konheim 研究生奖学金

代表性论著:
1.Lu Z, Xu S, Joazeiro C, Cobb MH, Hunter T. The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Molecular Cell. 9(5):945-56, (Highlighted in: Nat Rev Mol Cell Biol 2002;3:473; Nature-Signaling Update/the signaling gateway, 2002; and Faculty of 1000 Biology), 5/2002.

2.Lu Z, Ghosh S, Wang Z, Hunter T. Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 4(6):499-515 (Highlighted in: Nat Rev Cancer 2004; 4:90-91; Nature Signaling & Update/The signaling gateway 2004, and Faculty of 1000 Biology),

3.Xia Y, Wang J, Liu TJ, Yung WK, Hunter T, Lu Z. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis.  (Highlighted in Faculty of 1000 Biology; Selected as the feature article by Mol Cell and received MDACC Nycomed GmbH Outstanding Research Publication Award in 2007). Molecular Cell. 25(2):219-32, 1/2007. PMCID: PMC1829326.

4.Lu Z, Hunter T. Degradation of activated protein kinases by ubiquitination. Ann Rev Biochem. 78:435-75, 7/2009. PMCID: PMC2776765.

5.Zheng Y, Xia Y, Hawke D, Halle M, Tremblay ML, Gao X, Zhou XZ, Aldape K, Cobb MH, Xie K, He J, and Lu Z. FAK phosphorylation by ERK primes ras-induced tyrosine dephosphorylation of FAK mediated by PIN1 and PTP-PEST. Molecular Cell. 35(1):11-25 (Highlighted in Mol Cell and Faculty of 1000 Biology), 7/2009. PMCID: PMC2715139.

6.Ji H, Wang J, Nika H, Hawke D, Keezer S, Ge Q, Fang B, Fang X, Fang D, Litchfield DW, Aldape K, Lu Z. EGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-Catenin. Molecular Cell. 36(4):547-59 (Selected as the feature article by Mol Cell and highlighted in Cell and M.D. Anderson News Release), 11/2009. PMCID: PMC2784926.

7.Weiwei Yang, Yan Xia, Haitao Ji, Yanhua Zheng, Ji Liang, Wenhua Huang, Xiang Gao, Kenneth Aldape, Lu Z. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation. Nature. 2011480(7375):118-22, PMID: 22056988 (2011 Outstanding Research Publication Award at MD Anderson; HighlightedinCell Leading Edge, Nature SciBX, Science Signaling, Cancer Research, Cell Research, Chinese journal of Cancer, Future Oncology,and Faculty of 1000 Biology, and M.D. Anderson News Release).

8.Yang W, Xia Y, Hawke D,Li X, Liang J, Aldape K, Hunter T, Yung WK, and Lu Z.PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell. 8/2012; 150 (4): 685-696 (Listed in 2012: Signaling Breakthroughs of the Year, Science Signaling;Highlighted in Cell Leading Edge, Nature Reviews Cancer, Cancer Discovery, Cell Cycle,Faculty of 1000 Biology, and M.D. Anderson News Release).

9.Yang W, XiaY, CaoY, ZhengY, Bu W,Zhang L, You M, KohM, CoteG, Aldape K, LiY, Verma I, Chiao P,and Lu Z. EGFR-induced and PKCe monoubiquitylation-dependent NF-kB activation upregulates PKM2 expression and promotes turmorigenesis. Molecular Cell. 2012; 48(5):771-84 PMID:23123196 (Highlighted in Cancer Discovery and M.D. Anderson News Release)

10.Yang W, Zheng Y,Xia Y, Ji H, Chen X, Guo F, Lyssiotis C, Aldape K, Cantley L, and Lu Z. ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect. Nature Cell Biology. 12/2012;14(12):1295-304, PMID:23178880 (Highlighted in Nature Review Cancer 13, 5, 2013; Nature Chemical Biology;Cell Cycle and M.D. Anderson News Release)

11.Jiang Y, Li X, Yang W, Hawke D, Zheng Y, Xia Y, Aldape K, Wei C, Guo F, Chen Y, and Lu Z. PKM2 regulates chromosome segregation and mitosis progression of tumor cells. Molecular Cell. 1/2014. 53(1):75-87.PMID: 24316223 (Highlighted in Cancer Discovery and M.D. Anderson News Release).

13.Madarampalli B, Yuan Y, Liu D, Lengel K, Xu Y, Li G, Yang J, Li X, Lu Z, and Liu D. ATF5 connects the pericentriolar material to the proximal end of the mother centriole in the centrosome. Cell. 2015. 162(3):580-92. PMID: 26213385.

14.Jiang Y,Shen J,Wang Y, Qian X, Li X, Liu R,Xia Y, Chen Q, Peng G, Lin S, and Lu Z. Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. Nature Cell Biology. 2015. 7(9):1158-68. PMID: 26237645. (highlighted in Nature Cell Biology, Cancer Discovery, Science Signaling, and an MD Anderson news release).

15.Zheng Y, Li X, Qian X, Wang Y, Lee J, Xia Y, Hawke D, Zhang G, Lu J, and Lu Z. Secreted and O-GlcNAcylated MIF binds to the human EGF receptor and inhibits its activation. Nature Cell Biology. 2015.17(10):1348-55. PMID: 26280537 (highlighted in Cancer Discovery, Science Signaling, and an MD Anderson news release).

16.Ji H, Lee J, Wang Y, Pang Y, Zhang T, Xia Y, Zhong L, Lyu J, Lu Z. EGFR phosphorylates FAM129B to promote Ras activation. PNAS. 2016. 113(3):644-9.  PMID:26721396.

17.Li X, Jiang Y, Meisenhelder J, Yang W, Hawke D, Zheng Y, Xia Y, Aldape K, He J, Hunter T, Wang L, and Lu Z. Mitochondria-translocated phosphoglycerate kinase 1 functions as a protein kinase to coordinate glycolysis and TCA cycle in tumorigenesis.Molecular Cell. 2016. 61(5):705-719.PMID:26942675. (highlighted in MD Anderson news release).

18.Li X, Qian X, Peng L,Jiang Y, Hawke D,Zheng Y, Xia Y, Lee J, Cote G, Wang H,Wang L,QianC, and Lu Z. Splicing Switch from Ketohexokinase-C to Ketohexokinase-A drives hepatocellular carcinomagenesis. Nature Cell Biology. 2016. 18(5):561-71. PMID:2708854. (Highlighted in Cancer Discovery, Science Signaling, and an MD Anderson news release).

19.Liang J, Cao R, Xia Y, Zheng Y, Li X, Wang L, Yang W and Lu Z. PKM2 dephosphorylation by Cdc25A promotes the Warburg effect and tumorigenesis. Nature Communications. 2016. 7:12431. PMID: 27485204

20.Qian X, Li X, Cai Q, Zhang C, Yu Q, Jiang Y, Lee JH, Hawke D, Wang Y, Xia Y, Zheng Y, Jiang BH, Liu DX, Jiang T, Lu Z. Phosphoglycerate Kinase 1 Phosphorylates Beclin1 to Induce Autophagy.Molecular Cell. 3/2017. 2;65(5):917-931.PMID: 28238651 (Highlighted in Autophagy and an MD Anderson news release).

21.Xia Y, Yang W, Fa M, Li X, Wang Y, Jiang Y, Zheng Y, Ji H, Li J, and Lu Z. EGF-induced histone H3 polyubiquitylation and nucleosome disassembly promote gene expression and tumorigenesis. The Journal of Experimental Medicine. 2017. 214 (6), 1843-1855.PMID:28507061.

22.Li X,Yu W,Qian X, Xia Y, Zheng Y, Lee J, Li W, Lyu J, Rao G, Zhang X, Qian C, Rozen S, Jiang T, Lu Z. Nucleus-translocated ACSS2 promotes the gene transcription for lysosomal biogenesis and autophagy. Molecular Cell. 2017. 66(5):684-697.PMID:28552616. (Highlighted in Nature Reviews Molecular Cell Biology and an MD Anderson news release).

23.Lee JH, Liu R, Li J, Zhang C, Wang Y, Cai Q, Qian X, Xia Y, Zheng Y, Piao Y,Chen Q, Groot J, Tao Jiang T, Lu Z. Stabilization ofPhosphofructokinase 1 Platelet Isoform by AKT Promotes Tumorigenesis. Nature Communications. 2017.16;8(1):949.doi: 10.1038/s41467-017-00906-9. PMID: 29038421.

24.Qian X, Li X, Tan L, Lee JH, Xia X, Cai Q, Zheng Y, Wang H, Lorenzi P, Lu Z. Conversion of PRPS hexamer to monomer by AMPK-mediated phosphorylation inhibits nucleotide synthesis in response to energy stress. Cancer Discovery. 2017. PMID: 29074724.


25.Wang Y, Guo Y, Liu K, Liu R, Tan L, Yang P, Lee J, Du L,Xia Y, Li X,Hawke D, Zheng Y, He J, Xing D,Tao Y, Lu Z.KAT2A Coupled with the a-KGDH Complex Acts as a Histone H3 Succiny ltransferase. Nature. 2017. PMID: 29211711(Highlighted in Cancer Discovery, Faculty of 1000 Prime, andan MD Anderson news release).

26.Lu Z and Hunter T. Metabolic Kinases Moonlighting as Protein Kinases. Trends in Biochemical Sciences. 2018. (4):301-310. PMID: 29463470.

27.Lee JH, Liu R, Li J., Wang YG,Tan L, Li XJ, Qian X, Zhang C, Xia Y, Xu D, Guo W, Ding Z, Du L, Zheng y, Chen Q, Lorenzi PL, Mills GB, Jiang T, and Lu Z. EGFR-phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation. Molecular Cell. 4/2018. 19;70(2):197-210. PMID: 29677490.

28.Li X, Egervari G, Wang Y, Berger SL, Lu Z. Regulation of chromatin and gene expression by metabolic enzymes and metabolites. Nature Reviews Molecular Cell Biology. 2018.19(9):563-578. PMID: 29930302.

29.Li X, Qian X, Jiang H, Xia Y, Zheng Y, Li J, Huang BJ, Fang J, Qian CN, Jiang T, Zeng YX, and Lu Z. Nuclear PGK1 Alleviates ADP-Dependent Inhibition of CDC7 to Promote DNA Replication. Molecular Cell. 2018.72 (4): 650-660. PMID: 30392930.

30.Xu D, Li X, Lv G, Lv H, Lee J, Qian X, Wang Z, Xia Y, Du L, Cai Q, Zeng Y, Wang H, and Lu Z.The protein kinase activity of fructokinase Aspecifies the antioxidant responses of tumor cells by phosphorylating p62. Science Advances. 2019. 


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