Wei, Wenyi - Harvard Medical School - Beth Israel Deaconess Medical Center

个人简介

Professor, Pathology, Harvard Medical School Professor, Pathology, Beth Israel Deaconess Medical Center

研究领域

Aberrant cell cycle regulation leads to cancer development. Proper cell cycle transitions are driven by waves of ubiquitin-dependent degradation of key cell cycle regulators by APC or SCF, the two major E3 ligase complexes. My previous research demonstrated that APC/Cdh1 complex ubiquitinates and thus targets Skp2 for degradation in early G1 phase. This finding provides important insights into why SCF and APC activity is mutually exclusive and how the orchestration of SCF and APC activity affects cell cycle progression. More importantly, it also impinges on the function of Cdh1 as a tumor suppressor. I am also interested in understanding how SCF complexes regulate the G1-S transition by degradation of their specific substrates. Recently, I discovered that Fbw7 regulates the degradation of c-Jun in a GSK-3 phosphorylation dependent manner. My results assign a biological significance to the v-Jun S243F point mutation and also underscore the important function of Fbw7 in both cell proliferation and tumor suppression. The major focus of research in my laboratory is aimed at understanding how APC and SCF activities contribute towards cell cycle regulation and subsequent tumor formation. More specifically, I am interested in elucidating the underlying mechanisms that define the oscillation of APC and SCF activity in different cell cycle phases. Currently I am pursuing the underlying mechanisms that timely regulate APC/Cdh1 activity in different cell cycle phases. Additionally, I am also interested in understanding whether other layers of crosstalk between the APC and SCF complex exist. Furthermore, I would like to identify novel downstream targets for both APC and SCF complexes, which will help pinpoint their functions in both cell cycle control and tumor formation. To this end, I have developed biochemical purification approaches that would allow me to identify novel downstream targets for APC/Cdh1 and SCF/Fbw7 complexes. In addition, I am also interested in defining the tumor suppressor function of Cdh1 utilizing conditional Cdh1 knockout mice. To achieve these goals, my lab will use multidisciplinary approaches including biochemical and genetic analysis. In the long term, I hope that a better understanding of the multilayer regulation of the delicate proteolysis pathways will lead us to the design of more efficient intervention strategies to combat cancer and other diseases.

近期论文

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Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1.Zhang T, Xu D, Trefts E, Lv M, Inuzuka H, Song G, Liu M, Lu J, Liu J, Chu C, Wang M, Wang H, Meng H, Liu H, Zhuang Y, Xie X, Dang F, Guan D, Men Y, Jiang S, Jiang C, Dai X, Liu J, Wang Z, Yan P, Wang J, Tu Z, Babuta M, Erickson E, Hillis AL, Dibble CC, Asara JM, Szabo G, Sicinski P, Miao J, Lee YR, Pan L, Shaw RJ, Yuan J, Wei W.Science. 2023 Jun 30;380(6652):1372-1380. doi: 10.1126/science.abn1725. Cell cycle on the crossroad of tumorigenesis and cancer therapy.Liu J, Peng Y, Wei W.Trends Cell Biol. 2022 Jan;32(1):30-44. doi: 10.1016/j.tcb.2021.07.001. USP8 inhibition reshapes an inflamed tumor microenvironment that potentiates the immunotherapy.Xiong W, Gao X, Zhang T, Jiang B, Hu MM, Bu X, Gao Y, Zhang LZ, Xiao BL, He C, Sun Y, Li H, Shi J, Xiao X, Xiang B, Xie C, Chen G, Zhang H, Wei W, Freeman GJ, Shu HB, Wang H, Zhang J.Nat Commun. 2022 Mar 31;13(1):1700. doi: 10.1038/s41467-022-29401-6. ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy.Xiao X, Shi J, He C, Bu X, Sun Y, Gao M, Xiang B, Xiong W, Dai P, Mao Q, Xing X, Yao Y, Yu H, Xu G, Li S, Ren Y, Chen B, Jiang C, Meng G, Lee YR, Wei W, Freeman GJ, Xie C, Zhang J.Nat Commun. 2023 May 19;14(1):2859. doi: 10.1038/s41467-023-38605-3. PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity.Liu J, Bu X, Chu C, Dai X, Asara JM, Sicinski P, Freeman GJ, Wei W.Nat Commun. 2023 May 17;14(1):2806. doi: 10.1038/s41467-023-38443-3. The role of ubiquitination in tumorigenesis and targeted drug discovery.Deng L, Meng T, Chen L, Wei W, Wang P.Signal Transduct Target Ther. 2020 Feb 29;5(1):11. doi: 10.1038/s41392-020-0107-0. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy.Gao Y, Nihira NT, Bu X, Chu C, Zhang J, Kolodziejczyk A, Fan Y, Chan NT, Ma L, Liu J, Wang D, Dai X, Liu H, Ono M, Nakanishi A, Inuzuka H, North BJ, Huang YH, Sharma S, Geng Y, Xu W, Liu XS, Li L, Miki Y, Sicinski P, Freeman GJ, Wei W.Nat Cell Biol. 2020 Sep;22(9):1064-1075. doi: 10.1038/s41556-020-0562-4. Epub 2020 Aug 24. Ubiquitin signaling in cell cycle control and tumorigenesis.Dang F, Nie L, Wei W.Cell Death Differ. 2021 Feb;28(2):427-438. doi: 10.1038/s41418-020-00648-0. Epub 2020 Oct 31. High-fat diet promotes liver tumorigenesis via palmitoylation and activation of AKT.Bu L, Zhang Z, Chen J, Fan Y, Guo J, Su Y, Wang H, Zhang X, Wu X, Jiang Q, Gao B, Wang L, Hu K, Zhang X, Xie W, Wei W, Kuang M, Guo J.Gut. 2024 Jan 18:gutjnl-2023-330826. doi: 10.1136/gutjnl-2023-330826. Ring domains are essential for GATOR2-dependent mTORC1 activation.Jiang C, Dai X, He S, Zhou H, Fang L, Guo J, Liu S, Zhang T, Pan W, Yu H, Fu T, Li D, Inuzuka H, Wang P, Xiao J, Wei W.Mol Cell. 2023 Jan 5;83(1):74-89.e9. doi: 10.1016/j.molcel.2022.11.021. Lactate fuels mitosis.Dai X, Wei W.Mol Cell. 2023 May 18;83(10):1549-1551. doi: 10.1016/j.molcel.2023.04.013. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance.Zhang J, Bu X, Wang H, Zhu Y, Geng Y, Nihira NT, Tan Y, Ci Y, Wu F, Dai X, Guo J, Huang YH, Fan C, Ren S, Sun Y, Freeman GJ, Sicinski P, Wei W.Nature. 2018 Jan 4;553(7686):91-95. doi: 10.1038/nature25015. Targeting LYPLAL1-mediated cGAS depalmitoylation enhances the response to anti-tumor immunotherapy.Fan Y, Gao Y, Nie L, Hou T, Dan W, Wang Z, Liu T, Wei Y, Wang Y, Liu B, Que T, Lei Y, Zeng J, Ma J, Wei W, Li L.Mol Cell. 2023 Oct 5;83(19):3520-3532.e7. doi: 10.1016/j.molcel.2023.09.007. AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.Dai X, Jiang C, Jiang Q, Fang L, Yu H, Guo J, Yan P, Chi F, Zhang T, Inuzuka H, Asara JM, Wang P, Guo J, Wei W.Nat Metab. 2023 Feb;5(2):265-276. doi: 10.1038/s42255-022-00732-4. Epub 2023 Feb 2. WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.Lee YR, Yehia L, Kishikawa T, Ni Y, Leach B, Zhang J, Panch N, Liu J, Wei W, Eng C, Pandolfi PP.N Engl J Med. 2020 May 28;382(22):2103-2116. doi: 10.1056/NEJMoa1914919. PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.Jiang C, Liu J, He S, Xu W, Huang R, Pan W, Li X, Dai X, Guo J, Zhang T, Inuzuka H, Wang P, Asara JM, Xiao J, Wei W.Cell Metab. 2023 Dec 5;35(12):2183-2199.e7. doi: 10.1016/j.cmet.2023.11.001. S6K1-mediated phosphorylation of PDK1 impairs AKT kinase activity and oncogenic functions.Jiang Q, Zhang X, Dai X, Han S, Wu X, Wang L, Wei W, Zhang N, Xie W, Guo J.Nat Commun. 2022 Mar 22;13(1):1548. doi: 10.1038/s41467-022-28910-8. Targeting METTL3 reprograms the tumor microenvironment to improve cancer immunotherapy.Yu H, Liu J, Bu X, Ma Z, Yao Y, Li J, Zhang T, Song W, Xiao X, Sun Y, Xiong W, Shi J, Dai P, Xiang B, Duan H, Yan X, Wu F, Zhang WC, Lin D, Hu H, Zhang H, Slack FJ, He HH, Freeman GJ, Wei W, Zhang J.Cell Chem Biol. 2024 Apr 18;31(4):776-791.e7. doi: 10.1016/j.chembiol.2023.09.001. Epub 2023 Sep 25. Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.Zhang T, Xu D, Liu J, Wang M, Duan LJ, Liu M, Meng H, Zhuang Y, Wang H, Wang Y, Lv M, Zhang Z, Hu J, Shi L, Guo R, Xie X, Liu H, Erickson E, Wang Y, Yu W, Dang F, Guan D, Jiang C, Dai X, Inuzuka H, Yan P, Wang J, Babuta M, Lian G, Tu Z, Miao J, Szabo G, Fong GH, Karnoub AE, Lee YR, Pan L, Kaelin WG Jr, Yuan J, Wei W.Nat Cell Biol. 2023 Jul;25(7):950-962. doi: 10.1038/s41556-023-01170-4. Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway.Lee YR, Chen M, Lee JD, Zhang J, Lin SY, Fu TM, Chen H, Ishikawa T, Chiang SY, Katon J, Zhang Y, Shulga YV, Bester AC, Fung J, Monteleone E, Wan L, Shen C, Hsu CH, Papa A, Clohessy JG, Teruya-Feldstein J, Jain S, Wu H, Matesic L, Chen RH, Wei W, Pandolfi PP.Science. 2019 May 17;364(6441):eaau0159. doi: 10.1126/science.aau0159. Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.Dai X, Bu X, Gao Y, Guo J, Hu J, Jiang C, Zhang Z, Xu K, Duan J, He S, Zhang J, Wan L, Liu T, Zhou X, Hung MC, Freeman GJ, Wei W.Mol Cell. 2021 Jun 3;81(11):2317-2331.e6. doi: 10.1016/j.molcel.2021.03.037. Copper Promotes Tumorigenesis by Activating the PDK1-AKT Oncogenic Pathway in a Copper Transporter 1 Dependent Manner.Guo J, Cheng J, Zheng N, Zhang X, Dai X, Zhang L, Hu C, Wu X, Jiang Q, Wu D, Okada H, Pandolfi PP, Wei W.Adv Sci (Weinh). 2021 Sep;8(18):e2004303. doi: 10.1002/advs.202004303. SPOP-mediated ubiquitination and degradation of PDK1 suppresses AKT kinase activity and oncogenic functions.Jiang Q, Zheng N, Bu L, Zhang X, Zhang X, Wu Y, Su Y, Wang L, Zhang X, Ren S, Dai X, Wu D, Xie W, Wei W, Zhu Y, Guo J.Mol Cancer. 2021 Aug 5;20(1):100. doi: 10.1186/s12943-021-01397-5. RBR E3 ubiquitin ligases in tumorigenesis.Wang P, Dai X, Jiang W, Li Y, Wei W.Semin Cancer Biol. 2020 Dec;67(Pt 2):131-144. doi: 10.1016/j.semcancer.2020.05.002. Necroptosis pathways in tumorigenesis.Zhang T, Wang Y, Inuzuka H, Wei W.Semin Cancer Biol. 2022 Nov;86(Pt 3):32-40. doi: 10.1016/j.semcancer.2022.07.007. TF-DUBTACs Stabilize Tumor Suppressor Transcription Factors.Liu J, Yu X, Chen H, Kaniskan HÜ, Xie L, Chen X, Jin J, Wei W.J Am Chem Soc. 2022 Jul 20;144(28):12934-12941. doi: 10.1021/jacs.2c04824. Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer.Wang M, Liu J, Zhao Y, He R, Xu X, Guo X, Li X, Xu S, Miao J, Guo J, Zhang H, Gong J, Zhu F, Tian R, Shi C, Peng F, Feng Y, Yu S, Xie Y, Jiang J, Li M, Wei W, He C, Qin R.Mol Cancer. 2020 Aug 25;19(1):130. doi: 10.1186/s12943-020-01249-8. PRMT1 methylates METTL14 to modulate its oncogenic function.Wang J, Wang Z, Inuzuka H, Wei W, Liu J.Neoplasia. 2023 Aug;42:100912. doi: 10.1016/j.neo.2023.100912. Mitochondrial PD-L1 modulates cancer immunotherapy.Dai X, Liu J, Wei W.Cell Res. 2023 May;33(5):335-336. doi: 10.1038/s41422-023-00777-4. Targeted protein posttranslational modifications by chemically induced proximity for cancer therapy.Peng Y, Liu J, Inuzuka H, Wei W.J Biol Chem. 2023 Apr;299(4):104572. doi: 10.1016/j.jbc.2023.104572.