锌α2糖蛋白对线粒体生物合成相关因子的影响及其信号通路机制
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摘要
目的:构建重组小鼠锌α2糖蛋白(Zinc-α2-glycoprotein )真核表达载体,并稳定转染3T3-L1细胞,观察3T3-L1细胞过表达ZAG后对线粒体生物合成相关因子的影响。
方法:提取正常小鼠肝脏组织总RNA,通过RT-RCR方法扩增出ZAG序列,克隆入经XbaⅠ和HindШ双酶切后的pcDNA3.1(-),重组小鼠ZAG真核表达质粒(pcDNA3.1(-)-mZAG)经转化大肠杆菌JM109,筛选阳性克隆,酶切和核苷酸测序鉴定后经脂质体转染3T3-L1细胞,G418筛选阳性克隆扩增,RT-PCR法鉴定ZAG阳性细胞株并检测过氧化物酶增殖型受体γ辅助活化因子1α(PGC-1α)、核呼吸因子1/2(NRF-1/2)、线粒体转录因子A(mtTFA)mRNA表达,Western Blot检测PGC-1α、NRF1/2、mtTFA蛋白的表达。
结果:成功克隆小鼠ZAG cDNA全序列,并将其与pcDNA3.1(-)载体片段连接,构建成pcDNA3.1(-)-mZAG表达质粒。重组真核表达质粒经限制性核酸内切酶XbaⅠ和HindШ酶切后获得5.4kb和924bp两个片段,大小与理论值一致,并由核苷酸序列测定证实。pcDNA3.1(-)-mZAG成功转染3T3-L1细胞,在转染的3T3-L1细胞中ZAG基因的转录明显上调,过表达ZAG后,PGC-1α、NRF-1/2、mtTFA表达均上调。
结论:成功构建ZAG基因的真核表达质粒pcDNA3.1(-)-mZAG,构建ZAG稳定过表达细胞系,在稳定转染的3T3-L1细胞中,ZAGmRNA表达水平与线粒体生物合成有关,ZAG对线粒体生物合成相关因子PGC-1α、NRF-1/2、mtTFA的表达有促进作用。
目的:探讨锌α2糖蛋白(Zinc-α2-glycoprotein, ZAG)促进3T3-L1细胞线粒体生物合成相关因子的PKA和p38MAPK信号通路机制。
方法:体外培养3T3-L1细胞,分别加入ZAG、PKA抑制剂(H89)、H89+ZAG、p38MAPK抑制剂(SB203580)和SB203580+ZAG。应用RT-PCR法检测过氧化物酶增殖型受体γ辅助活化因子1α(PGC-1α)、核呼吸因子1/2(NRF-1/2)、线粒体转录因子A(mtTFA)的表达水平。
结果: RT-PCR法显示ZAG促进线粒体生物合成相关因子的表达,PKA特异性抑制剂H89和p38MAPK特异性抑制剂SB203580抑制线粒体生物合成相关因子的表达,而H89+ZAG和SB203580+ZAG处理细胞则抑制ZAG对线粒体生物合成相关因子的促进作用。
结论:ZAG能够促进线粒体生物合成相关因子的表达,这种作用可能是通过PKA和p38MAPK信号通路介导。
Objective: To construct pcDNA3.1(-)-mZAG recombinant mammalian expression vector , which was transfected into 3T3-L1 cell and observe its effects on relevant factors of mitochondria biogenesis after overexpression of ZAG.
Methods: The total RNA was extracted from mouse liver cell, and the sequence of ZAG was amplified with RT-PCR.The PCR product was then cloned into the prokaryotic expression vector pcDNA3.1(-) after enzyme by XbaⅠand HindШ. After identification by double restriction enzyme digestion and DNA sequencing, the recombinant eukaryotic expression plasmid pcDNA3.1(-)-mZAG was transfected into 3T3-L1 cell by lipofectamine 2000. The stable transfected 3T3-L1 cell line was established after selection with G418. The expression of ZAG mRNA and PGC-1α、NRF-1/2、mtTFA mRNA were detected by RT-PCR. The expression of PGC-1α、NRF-1/2、mtTFA protein were detected by Western Blot.
Results: Mouse ZAG coding sequence was amplified successfully and ligated with vector fragments by T4 ligase. The construction of pcDNA3.1(-)-mZAG plasmid containing mouse ZAG coding sequence of 5.4kb fragment and another 924bp fragment when digested by XbaⅠand HindШ. PcDNA3.1(-)-ZAG was transfected into the 3T3-L1 cell successfully, the expression of PGC-1α、NRF-1/2、mtTFA and ZAG mRNA were up-regulated in the transfected 3T3-L1 cell.
Conclusion: The recombinant eukaryotic expression vector pcDNA3.1(-)-ZAG was constructed successfully. The stable 3T3-L1 cell line over-expression of ZAG was established. In the stable transfected 3T3-L1 cell, the expression of ZAG mRNA is correlated with mitochondria generation, which have promote effects on expression of relevant factors of mitochondria biogenesis.
Objective: To explore whether PKA and p38MAPK could mediate the effects of ZAG on relevant factors of mitochondria biogenesis.
Methods: 3T3-L1 cells were treated with ZAG、PKA inhibitor H89、H89+ZAG、p38MAPK inhibitor SB203580 and SB203580+ZAG. The expression of PGC-1α、NRF-1/2、mtTFA mRNA and protein were detected by the method of RT-PCR and Western Blot.
Results: ZAG promoted the expression of relevant factors of mitochondria biogenesis, PKA inhibitor H89、p38MAPK inhibitor SB203580 inhibited the expression of relevant factors of mitochondria biogenesis, H89+ZAG、SB203580+ZAG decreased the promote effects of ZAG on mitochondria biogenesis.
Conclusion: ZAG have a promote effect on relevant factors of mitochondria biogenesis, PKA and p38MAPK signal pathway can mediate this effect.
方法:提取正常小鼠肝脏组织总RNA,通过RT-RCR方法扩增出ZAG序列,克隆入经XbaⅠ和HindШ双酶切后的pcDNA3.1(-),重组小鼠ZAG真核表达质粒(pcDNA3.1(-)-mZAG)经转化大肠杆菌JM109,筛选阳性克隆,酶切和核苷酸测序鉴定后经脂质体转染3T3-L1细胞,G418筛选阳性克隆扩增,RT-PCR法鉴定ZAG阳性细胞株并检测过氧化物酶增殖型受体γ辅助活化因子1α(PGC-1α)、核呼吸因子1/2(NRF-1/2)、线粒体转录因子A(mtTFA)mRNA表达,Western Blot检测PGC-1α、NRF1/2、mtTFA蛋白的表达。
结果:成功克隆小鼠ZAG cDNA全序列,并将其与pcDNA3.1(-)载体片段连接,构建成pcDNA3.1(-)-mZAG表达质粒。重组真核表达质粒经限制性核酸内切酶XbaⅠ和HindШ酶切后获得5.4kb和924bp两个片段,大小与理论值一致,并由核苷酸序列测定证实。pcDNA3.1(-)-mZAG成功转染3T3-L1细胞,在转染的3T3-L1细胞中ZAG基因的转录明显上调,过表达ZAG后,PGC-1α、NRF-1/2、mtTFA表达均上调。
结论:成功构建ZAG基因的真核表达质粒pcDNA3.1(-)-mZAG,构建ZAG稳定过表达细胞系,在稳定转染的3T3-L1细胞中,ZAGmRNA表达水平与线粒体生物合成有关,ZAG对线粒体生物合成相关因子PGC-1α、NRF-1/2、mtTFA的表达有促进作用。
目的:探讨锌α2糖蛋白(Zinc-α2-glycoprotein, ZAG)促进3T3-L1细胞线粒体生物合成相关因子的PKA和p38MAPK信号通路机制。
方法:体外培养3T3-L1细胞,分别加入ZAG、PKA抑制剂(H89)、H89+ZAG、p38MAPK抑制剂(SB203580)和SB203580+ZAG。应用RT-PCR法检测过氧化物酶增殖型受体γ辅助活化因子1α(PGC-1α)、核呼吸因子1/2(NRF-1/2)、线粒体转录因子A(mtTFA)的表达水平。
结果: RT-PCR法显示ZAG促进线粒体生物合成相关因子的表达,PKA特异性抑制剂H89和p38MAPK特异性抑制剂SB203580抑制线粒体生物合成相关因子的表达,而H89+ZAG和SB203580+ZAG处理细胞则抑制ZAG对线粒体生物合成相关因子的促进作用。
结论:ZAG能够促进线粒体生物合成相关因子的表达,这种作用可能是通过PKA和p38MAPK信号通路介导。
Objective: To construct pcDNA3.1(-)-mZAG recombinant mammalian expression vector , which was transfected into 3T3-L1 cell and observe its effects on relevant factors of mitochondria biogenesis after overexpression of ZAG.
Methods: The total RNA was extracted from mouse liver cell, and the sequence of ZAG was amplified with RT-PCR.The PCR product was then cloned into the prokaryotic expression vector pcDNA3.1(-) after enzyme by XbaⅠand HindШ. After identification by double restriction enzyme digestion and DNA sequencing, the recombinant eukaryotic expression plasmid pcDNA3.1(-)-mZAG was transfected into 3T3-L1 cell by lipofectamine 2000. The stable transfected 3T3-L1 cell line was established after selection with G418. The expression of ZAG mRNA and PGC-1α、NRF-1/2、mtTFA mRNA were detected by RT-PCR. The expression of PGC-1α、NRF-1/2、mtTFA protein were detected by Western Blot.
Results: Mouse ZAG coding sequence was amplified successfully and ligated with vector fragments by T4 ligase. The construction of pcDNA3.1(-)-mZAG plasmid containing mouse ZAG coding sequence of 5.4kb fragment and another 924bp fragment when digested by XbaⅠand HindШ. PcDNA3.1(-)-ZAG was transfected into the 3T3-L1 cell successfully, the expression of PGC-1α、NRF-1/2、mtTFA and ZAG mRNA were up-regulated in the transfected 3T3-L1 cell.
Conclusion: The recombinant eukaryotic expression vector pcDNA3.1(-)-ZAG was constructed successfully. The stable 3T3-L1 cell line over-expression of ZAG was established. In the stable transfected 3T3-L1 cell, the expression of ZAG mRNA is correlated with mitochondria generation, which have promote effects on expression of relevant factors of mitochondria biogenesis.
Objective: To explore whether PKA and p38MAPK could mediate the effects of ZAG on relevant factors of mitochondria biogenesis.
Methods: 3T3-L1 cells were treated with ZAG、PKA inhibitor H89、H89+ZAG、p38MAPK inhibitor SB203580 and SB203580+ZAG. The expression of PGC-1α、NRF-1/2、mtTFA mRNA and protein were detected by the method of RT-PCR and Western Blot.
Results: ZAG promoted the expression of relevant factors of mitochondria biogenesis, PKA inhibitor H89、p38MAPK inhibitor SB203580 inhibited the expression of relevant factors of mitochondria biogenesis, H89+ZAG、SB203580+ZAG decreased the promote effects of ZAG on mitochondria biogenesis.
Conclusion: ZAG have a promote effect on relevant factors of mitochondria biogenesis, PKA and p38MAPK signal pathway can mediate this effect.
引文
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[1].Burgi W, Schmid K. Preparation and properties of Zn-α2-glycoprotein of normal human plasma[J].J Biol Chem 1961, 236:1066– 74.
[2].Tzanavari T, Bing C, Trayhurn P.Postnatal expression of zinc-α2-glycoprotein in rat white and brown adipose tissue[J].Mol Cell Endocrinol,2007 ,279(1-2):26-33.
[3].Bao Y, Bing C, Hunter L, et al. Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed and secreted by human (SGBS) adipocytes[J]. FEBS Lett, 2005, 579(1):41–7.
[4].Rolli V, Radosavljevic M, Astier V, et al. Lipolysis is altered in MHC class I zinc-alpha(2)-glycoprotein deficient mice[J]. FEBS Lett, 2007, 581(3):394-400.
[5].Selva DM, Lecube A, Hernández C et al .Lower zinc-α2-glycoprotein production by adipose tissue and liver in obese patients unrelated to insulin resistance[J]. J Clin Endocrin Metab. 2009, 94(11):4499-507.
[6].Mracek T, Gao D, Tzanavari T,et al. Downregulation of zinc-α2-glycoprotein, a lipid mobilising factor, in adipose tissue and liver of obese ob/ob mice[J]. J Endocrinol,2010, 204(2):165-72.
[7]. Yeung DC, Lam KS, Wang Y, et al. Serum zinc-alpha2-glycoprotein correlates with adiposity, triglycerides and the key components of the metabolic syndrome in Chinese subjects[J]. J Clin Endocrin Metab, 2009, 58(10):1210-17.
[8].Ueyama H, Deng HX, Ohkubo I. Molecular cloning and chromosomal assignment of the gene for human Zn-a2-glycoprotein[J]. Biochemistry , 1993, 32(48):12968 -76.
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[11].Ring AE, Zabaglo L, Ormerod MG, et al. Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques[J]. Br J Cancer , 2005, 92(5):906-12.
[12].Bondar OP, Barnidge DR, Klee EW et al. LC-MS/MS Quantification of Zn-α2 Glycoprotein: A Potential Serum Biomarker for Prostate Cancer[J]. Clin Chem , 2007, 53(4):673-8.
[13].Abdul-Rahman PS, Lim B, Hashim OH. Expression of high-abundance proteins in sera of patients with endometrial and cervical cancers: analysis using 2-DE with silver staining and lectin detection methods[J]. Electrophoresis, 2007, 28(12):1989-96.
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[1].Burgi W, Schmid K. Preparation and properties of Zn-α2-glycoprotein of normal human plasma[J].J Biol Chem 1961, 236:1066– 74.
[2].Tzanavari T, Bing C, Trayhurn P.Postnatal expression of zinc-α2-glycoprotein in rat white and brown adipose tissue[J].Mol Cell Endocrinol,2007 ,279(1-2):26-33.
[3].Bao Y, Bing C, Hunter L, et al. Zinc-alpha2-glycoprotein, a lipid mobilizing factor, is expressed and secreted by human (SGBS) adipocytes[J]. FEBS Lett, 2005, 579(1):41–7.
[4].Rolli V, Radosavljevic M, Astier V, et al. Lipolysis is altered in MHC class I zinc-alpha(2)-glycoprotein deficient mice[J]. FEBS Lett, 2007, 581(3):394-400.
[5].Selva DM, Lecube A, Hernández C et al .Lower zinc-α2-glycoprotein production by adipose tissue and liver in obese patients unrelated to insulin resistance[J]. J Clin Endocrin Metab. 2009, 94(11):4499-507.
[6].Mracek T, Gao D, Tzanavari T,et al. Downregulation of zinc-α2-glycoprotein, a lipid mobilising factor, in adipose tissue and liver of obese ob/ob mice[J]. J Endocrinol,2010, 204(2):165-72.
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[8].Ueyama H, Deng HX, Ohkubo I. Molecular cloning and chromosomal assignment of the gene for human Zn-a2-glycoprotein[J]. Biochemistry , 1993, 32(48):12968 -76.
[9].Freije JP, Fueyo A, Uria JA, et al. Human Zn-a2-glycoprotein:complete genomicsequence, identification of a related pseudogene and relationship to class I major histocompatibility complex genes[J]. Genomics, 1993, 18(3):575-87.
[10].Araki T, Gejyo F, Takagaki K, et al. Complete amino acid sequence of human plasma Zn-a2-glycoprotein and its homology to histocompatibility antigens[J]. Proc Natl Acad Sci USA , 1988, 85(3):679-83.
[11].Ring AE, Zabaglo L, Ormerod MG, et al. Detection of circulating epithelial cells in the blood of patients with breast cancer: comparison of three techniques[J]. Br J Cancer , 2005, 92(5):906-12.
[12].Bondar OP, Barnidge DR, Klee EW et al. LC-MS/MS Quantification of Zn-α2 Glycoprotein: A Potential Serum Biomarker for Prostate Cancer[J]. Clin Chem , 2007, 53(4):673-8.
[13].Abdul-Rahman PS, Lim B, Hashim OH. Expression of high-abundance proteins in sera of patients with endometrial and cervical cancers: analysis using 2-DE with silver staining and lectin detection methods[J]. Electrophoresis, 2007, 28(12):1989-96.
[14].Garc1′a-Ram1′rez M, Canals F, Herna′ndez C, et al. Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy[J]. Diabetologia, 2007, 50(6):1294-303.
[15].Jain S, Rajput A, Kumar Y, et al. Proteomic analysis of urinary protein markers for accurate prediction of diabetic kidney disorder[J]. J Assoc Physicians India , 2005, 53:513-20.
[16].Varghese SA, Powell TB, Budisavljevic MN, et al. Urine biomarkers predict the cause of glomerular disease[J]. J Am Soc Nephrol , 2007, 18(3):913-22.
[17].Lopez-Boado YS, Diez-Itza I, Tolivia J, et al.Glucocorticoids and androgens up-regulate the Zn-a2-glycoprotein messenger RNA in human breast cancer cells[J]. Breast Cancer Res Treat, 1994, 29(3):247-58.
[18].Russell ST, Tisdale MJ. Effect of eicosapentaenoic acid (EPA) on expression of a lipid mobilizing factor in adipose tissue in cancer cachexia[J]. Prostaglandins Leukot Essent Fatty Acids, 2005, 72(6):409-14.
[19].Marrades MP, Martínez JA, Moreno-Aliaga MJ. ZAG, a lipid mobilizing adipokine, is downregulated in human obesity[J]. J Physiol Biochem, 2008, 64 (1):61-6.
[20].Mracek T, Ding Q, Tzanavari T, et al. The adipokine zinc-α2-glycoprotein is downregulated with fat mass expansion in obesity[J]. Clin Endocrinol (Oxf), 2010, 72(3):334-41.
[21].Bing C, Russell ST, Beckett EE, et al. Expression of uncoupling proteins-1, -2 and -3 mRNA is induced by an adenocarcinoma-derived lipid-mobilizing factor[J]. Br J Cancer, 2002, 86(4):612-8.
[22].Sanders PM, Tisdale MJ. Role of lipid-mobilising factor (LMF) in protecting tumour cells from oxidative damage[J]. Br J Cancer, 2004, 90(6):1274-8.