SENP3对不同程度氧化应激的感受和应答
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摘要
细胞在受到内源、外源的氧化物刺激时均能启动应答机制,改变蛋白质的量、定位和活性来抵抗应激。作者前期的研究发现,SUMO特异蛋白酶SENP3(Sentrin/SUMO specific protease3)可以感受一定程度的氧化应激而发生量的累积,从而影响一系列转录因子的SUMO化修饰状态和特异基因表达,发挥应答应激的功能,但在不同程度氧化应激时SENP3是否有不同的感受和应答机制并不清楚。该研究应用不同剂量H2O2模拟不同程度氧化应激,探讨SENP3的量、定位改变和对抗氧化蛋白表达的影响。结果显示,轻度氧化应激即可造成SENP3量的增加,但无H2O2剂量相关关系,而不同程度氧化应激均可引起SENP3从核仁向核质的移位,且随H2O2剂量增加而增加。在氧化应激引起的过氧化物氧还蛋白4(peroxiredoxin 4,Prx4)、超氧化物歧化酶1(superoxide dismutase1,SOD1)及过氧化氢酶(catalase,CAT)表达上调中,SENP3介导了这种表达改变,且有H2O2剂量相关性。该研究一方面发现了SENP3感受不同程度氧化应激的两种机制,另一方面也发现了SENP3介导抗氧化应答的功能,提示SENP3在细胞精细的应激应答机制中扮演了重要角色,具有一定的生理和病理意义。
In response to oxidation stress, proteins would alter their quantity, localization and activity to prevent from oxidative damage. Our previous study already discovered that SENP3(Sentrin/SUMO specific protease 3) sensed certain extent of oxidative stress via inhibiting degradation and then giving rise to alteration of sumolylation of transcription factors, by which tumor obtained potential of proliferation and migration. However, how SENP3 senses and makes responses to distinct extents of oxidative stress are unclear. In the present study, we treated tumor cells with different doses of hydrogen peroxide(H2O2) to mimic different extent of oxidative stress and therefore detected the quantity and localization of SENP3 and further analyzed the changes of antioxidants expression affected by SENP3. The results showed that SENP3 exhibited quick accumulation under low level of H2O2 and other levels of H2O2 in a dose independent manner. Notably, SENP3 also translocated from nucleolus to nucleoplasm upon H2O2 in dose dependent manner. Moreover, SENP3 mediated upregulation of antioxidants, peroxiredoxin 4(Prx4), superoxide dismutase 1(SOD1) and catalase(CAT) under different extents of oxidative stress. Taken together, SENP3 senses oxidative stress to be endowed with quantity regulation as well as localization regulation and then makes responses via gene expression regulation of specific antioxidants, indicating that SENP3 plays a critical role in elaborate redox maintenance and possesses physiology and pathology implications.
In response to oxidation stress, proteins would alter their quantity, localization and activity to prevent from oxidative damage. Our previous study already discovered that SENP3(Sentrin/SUMO specific protease 3) sensed certain extent of oxidative stress via inhibiting degradation and then giving rise to alteration of sumolylation of transcription factors, by which tumor obtained potential of proliferation and migration. However, how SENP3 senses and makes responses to distinct extents of oxidative stress are unclear. In the present study, we treated tumor cells with different doses of hydrogen peroxide(H2O2) to mimic different extent of oxidative stress and therefore detected the quantity and localization of SENP3 and further analyzed the changes of antioxidants expression affected by SENP3. The results showed that SENP3 exhibited quick accumulation under low level of H2O2 and other levels of H2O2 in a dose independent manner. Notably, SENP3 also translocated from nucleolus to nucleoplasm upon H2O2 in dose dependent manner. Moreover, SENP3 mediated upregulation of antioxidants, peroxiredoxin 4(Prx4), superoxide dismutase 1(SOD1) and catalase(CAT) under different extents of oxidative stress. Taken together, SENP3 senses oxidative stress to be endowed with quantity regulation as well as localization regulation and then makes responses via gene expression regulation of specific antioxidants, indicating that SENP3 plays a critical role in elaborate redox maintenance and possesses physiology and pathology implications.
引文
1 Stone JR,Yang S.Hydrogen peroxide:A signaling messenger.Antioxid Redox Signal 2006;8(3/4):243-70.
2 Finkel T,Holbrook NJ.Oxidants,oxidative stress and the biology of ageing.Nature 2000;408(6809):239-47.
3 Gao L,Mann GE.Vascular NAD(P)H oxidase activation in diabetes:A double-edged sword in redox signalling.Cardiovasc Res2009;82(1):9-20.
4 Cai H,Harrison DG.Endothelial dysfunction in cardiovascular diseases:the role of oxidant stress.Circ Res 2000;87(10):840-4.
5 D’Autreaux B,Toledano MB.ROS as signalling molecules:Mechanisms that generate specificity in ROS homeostasis.Nat Rev Mol Cell Biol 2007;8(10):813-24.
6 Wang Y,Yang J,Yi J.Redox sensing by proteins:Oxidative modifications on cysteines and the consequent events.Antioxid Redox Signal 2012;16(7):649-57.
7 Matthews DA,Olson MO.What is new in the nucleolus:Workshop on the nucleolus:New perspectives.EMBO Rep 2006;7(9):870-3.
8 Andersen JS,Lam YW,Leung AK,Ong SE,Lyon CE,Lamond AI,et al.Nucleolar proteome dynamics.Nature 2005;433(7021):77-83.
9 Boulon S,Westman BJ,Hutten S,Boisvert FM,Lamond AI.The nucleolus under stress.Mol Cell 2010;40(2):216-27.
10 Mayer C,Grummt I.Cellular stress and nucleolar function.Cell Cycle 2005;4(8):1036-8.
11 Yan S,Sun X,Xiang B,Cang H,Kang X,Chen Y,et al.Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90.EMBO J 2010;29(22):3773-86.
12 Sun Z,Hu S,Luo Q,Ye D,Hu D,Chen F.Overexpression of SENP3 in oral squamous cell carcinoma and its association with differentiation.Oncol Rep 2013;29(5):1701-6.
13 Wang Y,Yang J,Yang K,Cang H,Huang XZ,Li H,et al.The biphasic redox sensing of SENP3 accounts for the HIF-1 transcriptional activity shift by oxidative stress.Acta Pharmacol Sin 2012;33(7):953-63.
14 Ren YH,Liu KJ,Wang M,Yu YN,Yang K,Chen Q,et al.DeSUMOylation of FOXC2 by SENP3 promotes the epithelialmesenchymal transition in gastric cancer cells.Oncotarget 2014;5(16):7093-104.
15 Yun C,Wang Y,Mukhopadhyay D,Backlund P,Kolli N,Yergey A,et al.Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases.J Cell Biol 2008;183(4):589-95.
16 Castle CD,Cassimere EK,Denicourt C.LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis.Mol Biol Cell 2012;23(4):716-28.
17 Boddy MN,Howe K,Etkin LD,Solomon E,Freemont PS.PIC1 ,a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia.Oncogene 1996;13(5):971-82.
18 Gill G.SUMO and ubiquitin in the nucleus:Different functions,similar mechanisms?Genes Dev 2004;18(17):2046-59.
19 Muller S,Ledl A,Schmidt D.SUMO:A regulator of gene expression and genome integrity.Oncogene 2004;23(11):1998-2008.
20 Dou H,Huang C,van Nguyen T,Lu L,Yeh ET.SUMOylation and de-SUMOylation in response to DNA damage.FEBS Lett2011;585(18):2891-6.
21 Han Y,Huang C,Sun X,Xiang B,Wang M,Yeh ET,et al.SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress.J Biol Chem 2010;285(17):12906-15.
22 Higuchi M,Kato T,Chen M,Yako H,Yoshida S,Kanno N,et al.Temporospatial gene expression of Prx1 and Prx2 is involved in morphogenesis of cranial placode-derived tissues through epithelio-mesenchymal interaction during rat embryogenesis.Cell Tissue Res 2013;353(1):27-40.
23 Doufexi AE,Mina M.Signaling pathways regulating the expression of Prx1 and Prx2 in the chick mandibular mesenchyme.Dev Dyn 2008;237(11):3115-27.
24 Wood ZA,Schroder E,Robin HJ,Poole LB.Structure,mechanism and regulation of peroxiredoxins.Trends Biochem Sci2003;28(1):32-40.
25 Fujii J,Ikeda Y.Advances in our understanding of peroxiredoxin,a multifunctional,mammalian redox protein.Redox Rep 2002;7(3):123-30.
26 Zhang M,Hou M,Ge L,Miao C,Zhang J,Jing X,et al.Induction of peroxiredoxin 1 by hypoxia regulates heme oxygenase-1via NF-kappa B in oral cancer.PLo S One 2014;9(8):e105994.
27 Nishida T,Yamada Y.The nucleolar SUMO-specific protease SMT3IP1/SENP3 attenuates Mdm2-mediated p53 ubiquitination and degradation.Biochem Biophys Res Commun 2011;406(2):285-91.
28 Kuo ML,den Besten W,Thomas MC,Sherr CJ.Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3protease Senp3.Cell Cycle 2008;7(21):3378-87.
29 Messner S,Schuermann D,Altmeyer M,Kassner I,Schmidt D,Schar P,et al.Sumoylation of poly(ADP-ribose)polymerase 1inhibits its acetylation and restrains transcriptional coactivator functio.FASEB J 2009;23(11):3978-89.
30 Guo C,Hildick KL,Luo J,Dearden L,Wilkinson KA,Henley JM.SENP3-mediated de SUMOylation of dynamin-related protein 1 promotes cell death following ischaemia.EMBO J 2013;32(11):1514-28.
2 Finkel T,Holbrook NJ.Oxidants,oxidative stress and the biology of ageing.Nature 2000;408(6809):239-47.
3 Gao L,Mann GE.Vascular NAD(P)H oxidase activation in diabetes:A double-edged sword in redox signalling.Cardiovasc Res2009;82(1):9-20.
4 Cai H,Harrison DG.Endothelial dysfunction in cardiovascular diseases:the role of oxidant stress.Circ Res 2000;87(10):840-4.
5 D’Autreaux B,Toledano MB.ROS as signalling molecules:Mechanisms that generate specificity in ROS homeostasis.Nat Rev Mol Cell Biol 2007;8(10):813-24.
6 Wang Y,Yang J,Yi J.Redox sensing by proteins:Oxidative modifications on cysteines and the consequent events.Antioxid Redox Signal 2012;16(7):649-57.
7 Matthews DA,Olson MO.What is new in the nucleolus:Workshop on the nucleolus:New perspectives.EMBO Rep 2006;7(9):870-3.
8 Andersen JS,Lam YW,Leung AK,Ong SE,Lyon CE,Lamond AI,et al.Nucleolar proteome dynamics.Nature 2005;433(7021):77-83.
9 Boulon S,Westman BJ,Hutten S,Boisvert FM,Lamond AI.The nucleolus under stress.Mol Cell 2010;40(2):216-27.
10 Mayer C,Grummt I.Cellular stress and nucleolar function.Cell Cycle 2005;4(8):1036-8.
11 Yan S,Sun X,Xiang B,Cang H,Kang X,Chen Y,et al.Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90.EMBO J 2010;29(22):3773-86.
12 Sun Z,Hu S,Luo Q,Ye D,Hu D,Chen F.Overexpression of SENP3 in oral squamous cell carcinoma and its association with differentiation.Oncol Rep 2013;29(5):1701-6.
13 Wang Y,Yang J,Yang K,Cang H,Huang XZ,Li H,et al.The biphasic redox sensing of SENP3 accounts for the HIF-1 transcriptional activity shift by oxidative stress.Acta Pharmacol Sin 2012;33(7):953-63.
14 Ren YH,Liu KJ,Wang M,Yu YN,Yang K,Chen Q,et al.DeSUMOylation of FOXC2 by SENP3 promotes the epithelialmesenchymal transition in gastric cancer cells.Oncotarget 2014;5(16):7093-104.
15 Yun C,Wang Y,Mukhopadhyay D,Backlund P,Kolli N,Yergey A,et al.Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases.J Cell Biol 2008;183(4):589-95.
16 Castle CD,Cassimere EK,Denicourt C.LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis.Mol Biol Cell 2012;23(4):716-28.
17 Boddy MN,Howe K,Etkin LD,Solomon E,Freemont PS.PIC1 ,a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia.Oncogene 1996;13(5):971-82.
18 Gill G.SUMO and ubiquitin in the nucleus:Different functions,similar mechanisms?Genes Dev 2004;18(17):2046-59.
19 Muller S,Ledl A,Schmidt D.SUMO:A regulator of gene expression and genome integrity.Oncogene 2004;23(11):1998-2008.
20 Dou H,Huang C,van Nguyen T,Lu L,Yeh ET.SUMOylation and de-SUMOylation in response to DNA damage.FEBS Lett2011;585(18):2891-6.
21 Han Y,Huang C,Sun X,Xiang B,Wang M,Yeh ET,et al.SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress.J Biol Chem 2010;285(17):12906-15.
22 Higuchi M,Kato T,Chen M,Yako H,Yoshida S,Kanno N,et al.Temporospatial gene expression of Prx1 and Prx2 is involved in morphogenesis of cranial placode-derived tissues through epithelio-mesenchymal interaction during rat embryogenesis.Cell Tissue Res 2013;353(1):27-40.
23 Doufexi AE,Mina M.Signaling pathways regulating the expression of Prx1 and Prx2 in the chick mandibular mesenchyme.Dev Dyn 2008;237(11):3115-27.
24 Wood ZA,Schroder E,Robin HJ,Poole LB.Structure,mechanism and regulation of peroxiredoxins.Trends Biochem Sci2003;28(1):32-40.
25 Fujii J,Ikeda Y.Advances in our understanding of peroxiredoxin,a multifunctional,mammalian redox protein.Redox Rep 2002;7(3):123-30.
26 Zhang M,Hou M,Ge L,Miao C,Zhang J,Jing X,et al.Induction of peroxiredoxin 1 by hypoxia regulates heme oxygenase-1via NF-kappa B in oral cancer.PLo S One 2014;9(8):e105994.
27 Nishida T,Yamada Y.The nucleolar SUMO-specific protease SMT3IP1/SENP3 attenuates Mdm2-mediated p53 ubiquitination and degradation.Biochem Biophys Res Commun 2011;406(2):285-91.
28 Kuo ML,den Besten W,Thomas MC,Sherr CJ.Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3protease Senp3.Cell Cycle 2008;7(21):3378-87.
29 Messner S,Schuermann D,Altmeyer M,Kassner I,Schmidt D,Schar P,et al.Sumoylation of poly(ADP-ribose)polymerase 1inhibits its acetylation and restrains transcriptional coactivator functio.FASEB J 2009;23(11):3978-89.
30 Guo C,Hildick KL,Luo J,Dearden L,Wilkinson KA,Henley JM.SENP3-mediated de SUMOylation of dynamin-related protein 1 promotes cell death following ischaemia.EMBO J 2013;32(11):1514-28.
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