PAD4功能的研究进展及临床意义
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摘要
肽酰基精氨酸脱亚氨酶4(PAD4)是蛋白质翻译后的一种重要修饰酶,是PAD家族成员之一,主要分布于巨噬细胞、粒细胞与单核细胞的细胞质,可催化精氨酸转化为瓜氨酸残基。PAD4在心血管疾病、自身免疫性疾病和多种类型肿瘤中具有重要作用,尤其在心血管疾病和肿瘤方面的作用成为近年来研究的热点。PAD4的相关生物学功能以及与人类疾病的相关性使其可以作为相关人类疾病诊断及治疗的一个重要酶,但其在疾病的发生、发展以及预后中的具体机制仍不清楚,以PAD4为靶酶治疗临床疾病将成为研究热点。
Peptidylarginine deiminases 4( PAD4) is a modified enzyme after protein translation that belongs to the PAD family. PAD4 is mainly distributed in the cytoplasm of macrophages,granulocytes and monocytes,which can catalyze the conversion of arginine to citrulline residues. PAD4 plays a significant role in cardiovascular disease,autoimmune disease and multiple tumors,and the role of PAD4 in cardiovascular disease and neoplasms has been the focus of recent research. The related biological function of PAD4 and its relevance to human diseases make it an important enzyme for the diagnosis and treatment of related human diseases,but its specific mechanisms of action in the occurrence,development and prognosis of the diseases remain unclear. The treatment of the clinical diseases with PAD4 as target enzyme will become a hot research topic.
Peptidylarginine deiminases 4( PAD4) is a modified enzyme after protein translation that belongs to the PAD family. PAD4 is mainly distributed in the cytoplasm of macrophages,granulocytes and monocytes,which can catalyze the conversion of arginine to citrulline residues. PAD4 plays a significant role in cardiovascular disease,autoimmune disease and multiple tumors,and the role of PAD4 in cardiovascular disease and neoplasms has been the focus of recent research. The related biological function of PAD4 and its relevance to human diseases make it an important enzyme for the diagnosis and treatment of related human diseases,but its specific mechanisms of action in the occurrence,development and prognosis of the diseases remain unclear. The treatment of the clinical diseases with PAD4 as target enzyme will become a hot research topic.
引文
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[30]Li P,Yao H,Zhang Z,et al.Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4[J].Mol Cell Biol,2008,28(15):4745-4758.
[31]Yuji W,Pingxin L,Shu W,et al.Anticancer peptidylarginine deiminase(PAD)inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity[J].J Biol Chem,2012,287(31):25941-25953.
[32]Chang X,Han J,Pang L,et al.Increased PADI4 expression in blood and tissues of patients with malignant tumors[J].BMCCancer,2009,9(1):40.
[33]Slack JL,Causey CP,Thompson PR.Protein arginine deiminase4:A target for an epigenetic cancer therapy[J].Cell Mol Life Sci,2011,68(4):709-720.
[34]Nierodzik ML,Karpatkin S.Thrombin induces tumor growth,metastasis,and angiogenesis:Evidence for a thrombin-regulated dormant tumor phenotype[J].Cancer Cell,2006,10(5):355-362.
[35]常建芳,常晓天,赵燕,等.卵巢癌组织与患者血清中肽基精氨酸脱亚氨酶4和瓜氨酸化抗凝血酶表达的初步研究[J].中华肿瘤防治杂志,2008,15(15):1169-1172.
[36]Demers M,Wagner D.NETosis:A New Factor in Tumor Progression and Cancer-Associated Thrombosis[J].Semin Thromb Hemost,2014,40(3):277-283.
[37]Erpenbeck L,Sch9n MP.Neutrophil extracellular traps:Protagonists of cancer progression?[J].Oncogene,2017,36(18):2483.
[38]Wang J,Shi Q,Yuan TX,et al.Matrix metalloproteinase 9(MMP-9)in osteosarcoma:Review and meta-analysis[J].Clin Chim Acta,2014,433(7):225-231.
[39]Li H,Zhang K,Liu L,et al.A systematic review of matrix metalloproteinase 9 as a biomarker of survival in patients with osteosarcoma[J].Tumor Biol,2014,35(6):5487-5491.
[40]Houghton AM,Rzymkiewicz DM,Ji H,et al.Neutrophil elastasemediated degradation of IRS-1 accelerates lung tumor growth[J].Nat Med,2010,16(2):219-223.
[41]Wilson TJ,Nannuru KC,Futakuchi M,et al.Cathepsin G-mediated enhanced TGF-βsignaling promotes angiogenesis via upregulation of VEGF and MCP-1[J].Cancer Lett,2010,288(2):162-169.
[42]Cools-Lartigue J,Spicer J,Mc Donald B,et al.Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis[J].J Clin Invest,2013,123(8):3.446-3458.
[43]Cools-Lartigue J,Spicer J,Najmeh S,et al.Neutrophil extracellular traps in cancer progression[J].Cell Molr Life Sci,2014,71(21):4179-4194.
[2]Nakashima K,Hagiwara TM.Nuclear localization of peptidylarginine deiminase V and histone deimination in granulocytes[J].J Biol Chem,2002,277(51):49562-49568.
[3]Barnado A,Crofford LJ,Oates JC.At the Bedside:Neutrophil extracellular traps(NETs)as targets for biomarkers and therapies in autoimmune diseases[J].J Leukoc Biol,2016,99(2):265-278.
[4]Van Avondt K,Maegdefessel L,Soehnlein O.Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation[J].Thromb Haemost,2019,119(4):542-552.
[5]Chang X,Han J.Expression of peptidylarginine deiminase type 4(PAD4)in various tumors[J].Mol Carcinog,2006,45(3):183-196.
[6]Brinkmann V,Reichard U,Goosmann C,et al.Neutrophil extracellular traps kill bacteria[J].Science,2004,303(5663):1532-1535.
[7]Brill A,Fuchs TA,Savchenko AS,et al.Neutrophil extracellular traps promote deep vein thrombosis in mice[J].J Thromb Haemost,2012,10(1):136-144.
[8]Borissoff JI,Joosen IA,Versteylen MO,et al.Elevated levels of circulating DNA and chromatin are independently associated with severe coronary atherosclerosis and a prothrombotic state[J].Arterioscler Thromb Vasc Biol,2013,33(8):2032-2040.
[9]Chavanas S,Méchin MC,Takahara H,et al.Comparative analysis of the mouse and human peptidylarginine deiminase gene clusters reveals highly conserved non-coding segments and a new human gene,PADI 6[J].Gene,2004,330(330):19-27.
[10]Manjula B,Masashi M.Localization and expression of peptidylarginine deiminase 4(PAD4)in mammalian oocytes and preimplantation embryos[J].Zygote,2013,21(4):314-324.
[11]周剑涛,丁海峰.PAD4:一种治疗类风湿性关节炎的新靶酶[J].生命的化学,2008,28(6):737-739.
[12]Pasterkamp G,den Ruijter HM,Libby P.Temporal shifts in clinical presentation and underlying mechanisms of atherosclerotic disease[J].Nat Rev Cardiol,2017,14(1):21-29.
[13]Wang Y,Li M,Stadler S,et al.Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation[J].J Cell Biol,2009,184(2):205-213.
[14]Franck G,Mawson TL,Folco EJ,et al.Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury[J].Circ Res,2018,123(1):33-42.
[15]Franck G,Mawson T,Sausen G,et al.Flow Perturbation Mediates Neutrophil Recruitment and Potentiates Endothelial Injury via TLR2 in Mice:Implications for Superficial Erosion[J].Circ Res,2017,121(1):31-42.
[16]Stakos DA,Konstantinos K,Theocharis K,et al.Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction[J].Eur Heart J,2015,36(22):1405-1414.
[17]Liu Y,Carmona-Rivera C,Moore E,et al.Myeloid-Specific Deletion of Peptidylarginine Deiminase 4 Mitigates Atherosclerosis[J].Front Immunol,2018,9:1680.
[18]Warnatsch A,Ioannou M,Wang Q,et al.Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis[J].Science,2015,349(6245):316-320.
[19]Garcia-Romo GS,Caielli S,Vega B,et al.Netting Neutrophils Are Major Inducers of TypeⅠIFN Production in Pediatric Systemic Lupus Erythematosus[J].Sci Transl Med,2011,3(73):20-73.
[20]Lande R,Gregorio J,Facchinetti V,et al.Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide[J].Nature,2007,449(7162):564-569.
[21]Utz PJ,Hottelet M,Schur PH,et al.Proteins phosphorylated during stress-induced apoptosis are common targets for autoantibody production in patients with systemic lupus erythematosus[J].J Exp Med,1997,185(5):843-854.
[22]王增玲,邢广群,李春梅.系统性红斑狼疮患者血清肽酰基精氨酸脱亚胺酶4水平及意义[J].临床荟萃,2013,28(5):515-518.
[23]Trouw LA,Mahler M.Closing the serological gap:Promising novel biomarkers for the early diagnosis of rheumatoid arthritis[J].Autoimmun Rev,2012,12(2):318-322.
[24]Hoppe B,Haupl T,Egerer K,et al.Influence of peptidylarginine deiminase type 4 genotype and shared epitope on clinical characteristics and autoantibody profile of rheumatoid arthritis[J].Ann Rheum Dis,2009,68(6):898-903.
[25]Anzilotti C,Pratesi F,Tommasi C,et al.Peptidylarginine deiminase 4 and citrullination in health and disease[J].Autoimmun Rev,2010,9(3):158-160.
[26]吕卓,李娟,冯知涛,等.RA患者外周血HLA-DR4、PAD4、STAT4 mRNA表达及与疾病活动的相关性[J].南方医科大学学报,2010,30(6):1349-1353.
[27]Suzuki A,Kochi Y,Shoda H,et al.Decreased severity of experimental autoimmune arthritis in peptidylarginine deiminase type 4 knockout mice[J].Bmc Musculoskelet Disord,2016,17(1):205.
[28]Wei L,Wasilewski E,Chakka SK,et al.Novel Inhibitors of Protein Arginine Deiminase with Potential Activity in Multiple Sclerosis Animal Model[J].J Med Chem,2013,56(4):1715-1722.
[29]王增玲,商进春,李春梅,等.PAD4在抗中性粒细胞胞浆抗体相关性小血管炎中的作用及意义[J].北京大学学报(医学版),2014,46(2):200-206.
[30]Li P,Yao H,Zhang Z,et al.Regulation of p53 Target Gene Expression by Peptidylarginine Deiminase 4[J].Mol Cell Biol,2008,28(15):4745-4758.
[31]Yuji W,Pingxin L,Shu W,et al.Anticancer peptidylarginine deiminase(PAD)inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity[J].J Biol Chem,2012,287(31):25941-25953.
[32]Chang X,Han J,Pang L,et al.Increased PADI4 expression in blood and tissues of patients with malignant tumors[J].BMCCancer,2009,9(1):40.
[33]Slack JL,Causey CP,Thompson PR.Protein arginine deiminase4:A target for an epigenetic cancer therapy[J].Cell Mol Life Sci,2011,68(4):709-720.
[34]Nierodzik ML,Karpatkin S.Thrombin induces tumor growth,metastasis,and angiogenesis:Evidence for a thrombin-regulated dormant tumor phenotype[J].Cancer Cell,2006,10(5):355-362.
[35]常建芳,常晓天,赵燕,等.卵巢癌组织与患者血清中肽基精氨酸脱亚氨酶4和瓜氨酸化抗凝血酶表达的初步研究[J].中华肿瘤防治杂志,2008,15(15):1169-1172.
[36]Demers M,Wagner D.NETosis:A New Factor in Tumor Progression and Cancer-Associated Thrombosis[J].Semin Thromb Hemost,2014,40(3):277-283.
[37]Erpenbeck L,Sch9n MP.Neutrophil extracellular traps:Protagonists of cancer progression?[J].Oncogene,2017,36(18):2483.
[38]Wang J,Shi Q,Yuan TX,et al.Matrix metalloproteinase 9(MMP-9)in osteosarcoma:Review and meta-analysis[J].Clin Chim Acta,2014,433(7):225-231.
[39]Li H,Zhang K,Liu L,et al.A systematic review of matrix metalloproteinase 9 as a biomarker of survival in patients with osteosarcoma[J].Tumor Biol,2014,35(6):5487-5491.
[40]Houghton AM,Rzymkiewicz DM,Ji H,et al.Neutrophil elastasemediated degradation of IRS-1 accelerates lung tumor growth[J].Nat Med,2010,16(2):219-223.
[41]Wilson TJ,Nannuru KC,Futakuchi M,et al.Cathepsin G-mediated enhanced TGF-βsignaling promotes angiogenesis via upregulation of VEGF and MCP-1[J].Cancer Lett,2010,288(2):162-169.
[42]Cools-Lartigue J,Spicer J,Mc Donald B,et al.Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis[J].J Clin Invest,2013,123(8):3.446-3458.
[43]Cools-Lartigue J,Spicer J,Najmeh S,et al.Neutrophil extracellular traps in cancer progression[J].Cell Molr Life Sci,2014,71(21):4179-4194.