李晓涛

近年来对蛋白质研究领域的贡献：

   在REGγ（一种蛋白酶体激活因子）介导的非泛素依赖的蛋白酶体（proteasome）降解通路的研究中首次发现并证实了REGγ蛋白复合体的第一个生物学靶位点‚该发现突破了REGγ仅具有降解短肽链模型底物的禁区‚并提出了REGγ可以直接降解细胞内完整生物蛋白的新理论（Cell JAN.‚2006）。我们的最新研究（Mol.Cell June‚2007）进一步发现了REGγ-蛋白酶体的多种靶蛋白‚而这些蛋白质对细胞周期/肿瘤发生发展的调控起着重要的作用。这些研究结果都进一步揭示了REGγ介导的降解通路的生物学意义。

科研成果:

1.      Xie Y, Gao Y, Gao R, Yang W, Dong Z, Moses RE, Sun A, Li X*, Ge J*. The proteasome activator REGγ accelerates cardiac hypertrophy by declining PP2Acα-SOD2 pathway. Cell Death Differ.2020 Oct;27(10):2952-2972.

2.    Zhang B, Zhu X, Tian X, Yang M, Yu Y, Zhou Y, Gao Y, Zhang L, Li Z, Xiao Y, Moses RE, Li X. Procyanidin B2 promotes intestinal injury repair and attenuates colitis-associated tumorigenesis via suppression of oxidative stress in mouse.Antioxid Redox Signal. 2020 Sep 17.

3.      Gao X, Wang Q, Wang Y, Liu J, Liu S, Liu J, Zhou X, Zhou L, Chen H, Pan L, Chen J, Wang D, Zhang Q, Shen S, Xiao Y, Wu Z, Cheng Y, Chen G, Kubra S, Qin J, Huang L, Zhang P, Wang C, Moses RE, Lonard DM, O' Malley BW, Fares F, Zhang B, Li X*, Li L*, Xiao J* NIP30, a REGg inhibitor, accentuates anticancer sensitivity in p53-deficient tumor cells. 2020 Nature Communications. 2020 Aug 6;11(1):3904. 

4.      Xie Y, Li X, Ge J. STAT3-CyPA signaling pathway in endothelial cell apoptosis. Cell Signal. 2020 Jan; 65:109413.

5.      Tong L, Shen S, Huang Q, Fu J, Wang T, Pan L, Zhang P, Chen G, Huang T, Li K, Liu Q, Xie S, Yang X, Moses RE, Li X*, Li L*. Proteasome-dependent degradation of Smad7 is critical for lung cancer metastasis. Cell Death Differ. 2019 Nov 26.

6.      Wang J, Xing Y, Wang Y, He Y, Wang L, Peng S, Yang L, Xie J, Li X, Qiu W, Yi Z, Liu M. A novel BMI-1 inhibitor QW24 for the treatment of stem-like colorectal cancer. J Exp Clin Cancer Res. 2019 Oct 22;38(1):422.

7.      Zhou L, Yao L, Zhang Q, Xie W, Wang X, Zhang H, Xu J, Lin Q, Li Q, Xuan Y, Ji L, Wang L, Wang W, Wang W, Shi T, Fang L, Zheng B, Li L, Liu S, Zhang B, Li X. REGγ controls Th17 cell differentiation and autoimmune inflammation by regulating dendritic cells. Cell Mol Immunol. 2019 Sep 11.

8. Xie Y, Li X, Ge J. Expression of REGγ in atherosclerotic plaques and promotes endothelial cells apoptosis via the cyclophilin A pathway indicates functional implications in atherogenesis.Cell Cycle. 2019 Sep;18(17):2083-2098.

9.      Yao L, Zhou L, Xuan Y, Zhang P, Wang X, Wang T, Meng T, Xue Y, Ma X, Shah AS, Shang S, Ma X, Xie W, Wang H, Fu Q, Xia Y, Moses RE, Wang H, Li L, Xiao J, Zhang B, Li X. The proteasome activator REGγ counteracts immunoproteasome expression and autoimmunity. J Autoimmun. 2019 Sep;103:102282.

10.  Xie Y, Li X, Ge J. Cyclophilin A-FoxO1 signaling pathway in endothelial cell apoptosis. Cell Signal. 2019 Sep;61:57-65.

11.  Gao X, Chen H, Liu J, Shen S, Wang Q, Clement TM, Deskin BJ, Chen C, Zhao D, Wang L, Guo L, Ma X, Zhang B, Xu Y, Li X*, Li L*. The REGγ-Proteasome Regulates Spermatogenesis Partially by P53-PLZF Signaling. Stem Cell Reports. 2019 Jul 30. pii: S2213-6711(19)30262-0.

12.  Jiao C, Li L, Zhang P, Zhang L, Li K, Fang R, Yuan L, Shi K, Pan L, Guo Q, Gao X, Chen G, Xu S, Wang Q, Zuo D, Wu W, Qiao S, Wang X, Moses R, Xiao J, Li L, Dang Y, Li X. REGγ ablation impedes dedifferentiation of anaplastic thyroid carcinoma and accentuates radio-therapeutic response by regulating the Smad7-TGF-β pathway. Cell Death Differ. 2019 Jun 26.

13.  Chen S, Wang Q, Wang L, Chen H, Gao X, Gong D, Ma J, Kubra S, Yao X, Li X, Li L, Zhai W, Zheng J. REGγ deficiency suppresses tumor progression via stabilizing CK1ε in renal cell carcinoma. Cell Death Dis. 2018 May 24;9(6):627

14.  Qingwei Wang, Xiao Gao, Lei Yuan, Tong Yu, etal., Lei Li, Yongyan Dang, Li X. REGγ controls the Hippo-YAP signaling and reciprocal NF-kB–Yap regulation to promote colon cancer. Clinical Cancer Research. 2018  Apr 15;24(8):2015-2025

15.  Zuo Q, Cheng S, Huang W, Bhatti MZ, Xue Y, Zhang Y, Zhang B, Li L, Wu L, Fu J, Chen J, Li X. REGγ Contributes to Regulation of Hemoglobin and Hemoglobin δ Subunit. Oxid Med Cell Longev 2017;2017:7295319.

16.  Xu J, Jiao J, Xu W, Ji L, Jiang D, Xie S, Kubra S, Li X, Fu J, Xiao J, Zhang B. Mutant p53 promotes cell spreading and migration via ARHGAP44. Sci China Life Sci 2017 Sep;60(9):1019-1029.

17.  Chen S, Wang L, Yao X, Chen H, Xu C, Tong L, Shah A, Huang T, Chen G, Chen J, Liu TL, Li X, Zheng JH, Li L. miR-195-5p is critical in REGγ-mediated regulation of wnt/β-catenin pathway in renal cell carcinoma. Oncotarget 2017 Jul 15;8(38):63986-64000.

18.  Dong H, Xu J, Li W, Gan J, Lin W, Ke J, Jiang J, Du L, Chen Y, Zhong X, Zhang D, Yeung SJ, Li X, Zhang H, Reciprocal androgen receptor/interleukin-6 crosstalk drives oesophageal carcinoma progression and contributes to patient prognosis，J Pathol 2017Mar; 241(4): 448-46.

19.  Wan Z, Jiang D, Chen S, Jiao J, Ji L, Shah AS, Wei H, Yang X, Li X, Wang Y, Xiao J. T-box transcription factor brachyury promotes tumor cell invasion and metastasis in non-small cell lung cancer via upregulation of matrix metalloproteinase 12. Oncol Rep. 2016 Jul;36(1):306-14. 

20.  Xu J, Zhou L, Lei Li, Moses RE, O'Malley BW,Li X. The REGgamma-proteasome forms a regulatory circuit with IĸBepsilon and NFκB in experimental colitis. Nature Communications 2016 Feb. 22；7:10761.

21.  Sun J, Luan Y, Xiang D, Tan X, Chen H, Deng Q, Zhang J, Chen M, Huang H, Wang W, Niu T, Li W, Peng H, Li S, Li L, Tang W, Li X*, Wu D*, Wang P*. The 11S Proteasome Subunit PSME3 Is a Positive Feedforward Regulator of NF-κB and Important for Host Defense against Bacterial Pathogens. Cell Rep. 2016 Feb 2;14(4):737-49.

22.  Klionsky DJ et al (over 1000 authors). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016 Jan 2;12(1):1-222.

23.  Fan G, Sun L, Shan P, Zhang X, Huan J, Zhang X, Li D, Wang T, Wei T, Zhang X, Gu X, Yao L, Xuan Y, Hou Z, Cui Y, Cao L, Li X, Zhang S, Wang C. Loss of KLF14 triggers centrosome amplification and tumorigenesis. Nature Communications 2015 Oct 6;6:8450.

24.  Lv Y, Meng B, Dong H, Jing T, Wu N, Yang Y, Huang L, Moses RE, O'Malley BW, Mei B, Li X. Up-regulation of GSK3β Contributes to Brain Disorders in Elderly REGγ-knockout Mice. Neuropsychopharmacology. 2015 Sept 15.

25.  Shuangxi Li, Cong Jiang, Jingjing Pan, Xinbo Wang, Jiali Jin, Linlin Zhao, Weijuan Pan, Guanghong Liao, Xiaopan Cai, Li X, Jianru Xiao, and Ping Wang  Regulation of c-Myc protein stability by proteasome activator REGγ. Cell Death and Differentiation. 2015 Jun;22(6):1000-11.

26.  Ji L, Xu J, Liu J, Amjad A, Liu Q, Li X. Mutant p53 promotes tumor cell malignancy by both positive and negative regulation of TGF-β pathway. J Biol Chem. 2015 May 1;290(18):11729-40.

27.  Yuanyuan Zhang, Shuang Liu, Qiu Hong Zuo, Lin Wu, Lei Ji, Wanli Zhai, Jianru Xiao, Jiwu Chen, and Li X.Oxidative challenge enhances REGγ-proteasome dependent protein degradation. Free Radical Biology & Medicine 2015 May;82:42-9.

28.  Amjad Ali, Pei Zhang, Yao Liangfang, Sun Wenshe, Hao Wang, Xia Lin, Yan Dai, Xin-hua Feng, Robb Moses, Daxin Wang, Li X*,Jianru Xiao*.  KLF17 empowers TGF-β/Smad signaling by targeting Smad3-dependent pathway to suppress tumor growth and metastasis during cancer progression Cell Death & Disease 2015 Mar 12; 6.

29.  Li L, Dang Y, Xiao J, Moses RE, & Li X. (2015). REGg is critical for skin carcinogenesis by modulating Wnt/β-catenin pathway. Nature Communications2015 Apr 24;6:6875.

30.  Li X*, Jianping Jin, Weiguo Cao, Carlos Caulin, Robb E. Moses Stresses, Aging, and Age-Related Disorders.Oxidative Medicine and Cellular Longevity2015 Special edition, Vol. 2014 (Article ID 320564).

31.  Liu S, Lai L, Zuo Q, Dai F, Wu L, Wang Y, Liu M, Yi Z, Xiao J, Li X. PKA turnover by the REGγ-proteasome modulates FoxO1 cellular activity and VEGF-induced angiogenesis.J Mol Cell Cardiol. 2014 Feb 20; 72C: 28-38.

32.  Shi J, Wong J, Piesik P, Fung G, Zhang J, Jagdeo J, Li X, Jan E, Luo H. Cleavage of sequestosome 1/p62 by an enteroviral protease results in disrupted selective autophagy and impaired NFKB signaling.Autophagy. 2013 Aug 13;9 (10).

33.  Ali A,  Wang Z,  Ji L, Liu J, Li L, Yang Y, Wang Y, Zhou L,  Guo L, Wang H, Chen J, Caulin C, Myers JN, Fu J, Xiao J, Zhang B, Li X.WT-p53/TGF-β signaling and mutant-p53 differentially regulates REGγ to target ubiquitin/ATP-independent REGγ-proteasome pathway during cancer progression. Nature Communications 2013 4:2667.

34.  Dong S, Jia C, Zhang S, Fan G, Xiao W, Shan P, Sun L, Li L, Zheng Y, Liu J, Li Y, Wei H, Hu C, Zhang W, Li Q, Liu J, Jia F, Mo Q, Edwards DP, Huang S, Chan L, O'Malley BW, Li X* and Wang C* The REGγ Proteasome Regulates Hepatic Lipid Metabolism through Inhibition of Autophagy. Cell Metabolism2013 Sep 3;18(3):380-91. 

35.  Li L, Zhao D, Wei H, Yao L, Dang Y, Amjad A, Xu J, Liu J, Guo L, Li D, Li Z, Zuo D, Zhang Y, Liu J, Huang S, Jia C, Wang L, Wang Y, Xie Y, Luo J, Zhang B, Luo H, Donehower LA, Moses RE, Xiao J, O'Malley BW, Li X. REGγ deficiency promotes premature aging via the casein kinase 1 pathway.ProcNatl Acad Sci U S A. 2013 Jul 2;110(27):11005-10.

36.  Liu J, Wang Y, Li L, Zhou L, Wei H, Zhou Q, Liu J, Wang W, Ji L, Shan P, Wang Y, Yang Y, Jung SY, Zhang P, Wang C, Long W, Zhang B, Li X. Site-specific acetylation of the proteasome activator REGγ directs its heptameric structure and functions. J Biol Chem. 2013 Jun 7;288(23):16567-78

37.  Redfern AD, Colley SM, Beveridge DJ, Ikeda N, Epis MR, Li X, Foulds CE, Stuart LM, Barker A, Russell VJ, Ramsay K, Kobelke SJ, Li X, Hatchell EC, Payne C, Giles KM, Messineo A, Gatignol A, Lanz RB, O'Malley BW, Leedman PJ. RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators.Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6536-41. 

38.  Jing He, Long Cui, Yu Zeng, Guangqiang Wang, Li X. (2012).  REGγ is associated with multiple oncogenic pathways in human cancers. BMC Cancer. Feb 23; 12(1):75.

39.  Qiao S, Murakami K, Zhao Q, Wang B, Seo H, Yamashita H, Li X, Iwamoto T, Ichihara M, Yoshino M. (2012). Mimosine-Induced Apoptosis in C6 Glioma Cells Requires the Release of Mitochondria-Derived Reactive Oxygen Species and p38, JNK Activation. Neurochem Res. Feb;37(2):417-27.

40.  Shen J, Zhang S, Li Y, Zhang W, Chen J, Zhang M, Wang T, Jiang L, Zou X, Wong J, Li X, Cui Y, Wang C. (2011). p14(ARF) inhibits the functions of adenovirus E1A oncoprotein. Biochem J. Mar 1;434(2):275-85.

41.  Wu Y, Wang L, Zhou P, Wang G, Li X. (2011).  Regulation of REGg cellular distribution and function by SUMO modification.Cell Research.  2011 May; 21(5):807-16.

42.  Gao G, Wong J, Zhang J, Mao I, Shravah J, Wu Y, Xiao A, Li X*, Luo H*. (2010). Proteasome Activator REGg Enhances Coxsackieviral Infection via Facilitating p53 Degradation. J. Virol.84 (21): 11056-11066. 

43.  Liu J, Yu G., Zhao P., Wang C., Luo H., Long W., Wang Y., Zhao Y., Tsai M., O'Malley B.W. and Li X. (2010).  REGγ modulates p53 activity by regulating its cellular localization. J. Cell Science.123 (pt23): 4076-84.

44.  Tian M, Xiaoyi W, Li X, Guosheng R. (2009). Proteasomes reactivator REGγ enchances oncogenicity of MDA-MB-231 cell line via promoting cell proliferation and inhibiting apoptosis.Cell Mol Biol(Noisy-le-grand). 55 Suppl:OL1121-31.

45.  Yu G, Zhao Y, He J, Mukherjee A, Mao CA, Li M, and Li X. (2008). Comparative analysis of REGγ expression augurs functional implication. J. Mol. Cell. Biol.Aug; 2(4):192-8.

46.  Ivy Mao, Jian Liu, Li X*, Honglin Luo*. (2008). REGg, A Proteasome Activator and Beyond? Cell and Mol Life Sci. Dec;65(24):3971-80.

47.  Li X, Larbi Amazit, Weiweng Long, David M. Lonard, John J. Monaco and O’Malley B.W. (2007). Proteolytic turnover of p21 by the REGγ-proteasome pathway. Mol. Cell,26,  831-842

48.  Li X., Lonard D., Jung S.Y., Malovannaya A., Feng Q., Qin J., Tsai S. Y., Tsai M-J., and O’Malley B.W. (2006).  The SRC-3/AIB1 coactivator is degraded in an ubiquitin- and ATP-independent manner by the REGgamm-proteasome  Cell. 124, 381-392.

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50.  Li X. Lonard D. M. and O’Malley B. W. (2004).  A Contemporary Understanding of Progesterone Receptor Function (Review). Mechanisms of Aging and Development. 125, 669-78.

51.  Auboeuf D., Dowhan D.H., Li X., Larkin K., Ko L., Berget S.M., O'Malley B.W.(2004). CoAA, a Nuclear Receptor Coactivator Protein at the Interface of Transcriptional Coactivation and RNA Splicing.Mol. Cell. Biol.24, 442-53.

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53.  Li X., Wong J., Tsai S.Y., Tsai M.J., and O'Malley B.W. (2003). Progesterone and glucocorticoid receptors recruit distinct coactivator complexes and promote distinct patterns of local chromatin modification. Mol. Cell. Biol.23, 3763-73.

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