MAPK1和eEF1B对奶牛乳腺上皮细胞泌乳调控作用及机理研究
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摘要
我国是一个奶业大国，但奶牛产奶量低、发病率高严重制约着我国奶牛养殖业的发展，如何提高乳产量及乳蛋白含量成为我们亟待解决的问题。蛋氨酸和赖氨酸是乳蛋白合成的重要前体物质，以前的研究主要侧重于蛋氨酸和赖氨酸对奶牛生产性能的影响，而对体外培养的奶牛乳腺上皮细胞的促进泌乳和增殖作用研究较少。为了确定泌乳期奶牛乳蛋白合成的功能基因，揭示重要功能基因在乳蛋白合成中的作用机制，建立乳腺中乳蛋白合成的基因调控网络，以及在细胞信号转导调控中的作用，为建立乳腺泌乳调控技术提供基本理论依据和研究技术方法。
本研究采用组织块儿培养法，成功构建了体外培养的奶牛乳腺上皮细胞模型，应用CASY细胞分析仪检测了不同浓度和作用时间下蛋氨酸和赖氨酸对奶牛乳腺上皮细胞活力的影响，利用高效液相色谱检测了β-casein的分泌情况，确定了蛋氨酸和赖氨酸最佳剂量分别为0.6mmol/L和1.2mmol/L，最佳作用时间为24h。建立奶牛乳腺上皮细胞核磷酸化蛋白质组技术，应用双向电泳（2-DE）结合质谱技术（MALDI-TOF-MS）鉴定蛋氨酸和赖氨酸对奶牛乳腺上皮细胞核磷酸化蛋白质的差异影响，发现蛋氨酸处理组，Staphylococcal nucleasedomain-containing protein1、Glycyl-tRNA synthetase、Septin-6、Twinfilin-1和Elongationfactor1-beta （eEF1B）蛋白质表达上调，赖氨酸处理组，SKIV2L2、sec-related protein D、T-complex protein1subunit delta、protein disulfide-isomerase A3、coronin actin binding protein1C和mitogen-activated protein kinase1（MAPK1）蛋白质表达上调；并应用荧光定量PCR和Western blotting技术验证差异蛋白在转录水平和蛋白水平上的表达，与2-DE结果一致。实验过程中，采用基因沉寂技术，qRT-PCR鉴定eEF1B（P<0.05）和MAPK1基因沉寂有效（P<0.01），应用Western blotting检测了沉寂eEF1B后，mTOR（P<0.05）、Phospho-mTOR（P<0.05）、GARS（P<0.05）和SND1（P<0.05）蛋白表达降低，并且差异显著，而Stat5（P>0.05）和Phospho-Stat5（P>0.05）蛋白表达稍有降低，但差异不显著；高效液相色谱检测β-酪蛋白含量增加，并且差异显著（P<0.05）。沉寂MAPK1后，mTOR（P<0.05）、Phospho-mTOR（P<0.01）、S6K1（P<0.05）、Phospho-S6K1（P<0.05）、Stat5（P<0.05）和Phospho-Stat5（P<0.05）蛋白表达降低，并且差异显著；高效液相色谱检测β-酪蛋白含量增加，并且差异极其显著（P<0.01）。采用基因过表达技术，qRT-PCR鉴定eEF1B（P<0.01）和MAPK1基因表达增高（P<0.05），应用Western blotting检测了过表达eEF1B后，mTOR（P<0.05）、Phospho-mTOR（P<0.05）、GARS（P<0.05）和SND1（P<0.05）蛋白表达降低，并且差异显著，而Stat5（P>0.05）和Phospho-Stat5（P>0.05）蛋白表达变化不明显；高效液相色谱检测β-酪蛋白含量增加，但差异不显著（P>0.05）。过表达MAPK1后，mTOR（P<0.05）、Phospho-mTOR（P<0.05）、S6K1（P<0.05）和Stat5（P<0.01）蛋白表达升高，并且差异显著；而Phospho-S6K1、Phospho-Stat5蛋白表达升高，但差异不显著（P>0.05）；高效液相色谱检测β-酪蛋白含量增加，并且差异极其显著（P<0.01）。实验过程中通过G418筛选获得稳定转染pGCMV-IRES-EGFP-eEF1B和pGCMV-IRES-EGFP-MAPK1的细胞株，稳定转染细胞后，分别添加蛋氨酸和赖氨酸，应用Western blotting检测了mTOR（P<0.05）和Phospho-mTOR（P<0.05）的表达变化，发现蛋氨酸和赖氨酸营养素可以通过调节MAPK1和eEF1B介导mTOR信号转导通路，进而调节乳蛋白的表达。应用细胞免疫沉淀和GST-pull down技术并联合质谱鉴定与MAPK1相互作用的蛋白有ARPC4、β-enolase、Annexin A2、Small G protein signaling modulator1和PolymeraseI and transcript release factor；与eEF1B相互作用的蛋白有14-3-3theta、Heat shock protein、eEF1A1、Small nuclear ribonucleoprotein polypeptide A和40S ribosomal protein S4。
以上实验结果为奶牛营养基因组学的研究提供了理论依据和技术方法。
China is a country of milk, but milk yield is low, a high incidence of seriously restricting thedevelopment of China's dairy industry, how to improve the milk yield and quality has become anurgent problem. Methionine and lysine are important precursors of milk protein synthesis, previousstudies mainly focused on the effects of methionine and lysine on production performance of dairycows, while the effects of lactation regulation on dairy cow mammary gland epithelial cells(DCMECs) are poorly researched. In order to determine genes of milk protein synthesis in dairycows and reveal the mechanism of important functional genes in milk protein synthesis haveimportant basic theory and research methods by regulating mammary gland development.
A dairy cow mammary epithelial cell line was established through culture method of tissueblock and detection of cell biological characters. Effects of methionine and lysine on viabilitiesand β-casein of DCMECs were evaluated by CASY and HPLC, and determined the optimal dose ofmethionine and lysine was0.6mmol/L and1.2mmol/L, the best time was24h. A nuclearphosphoproteomics of DCMECs was successfully established, five proteins for which expressionwas significantly increased in methionine-treated DCMECs were selected, the5up-regulatedexpressed phosphoproteins included staphylococcal nuclease domain-containing protein1(SND1),Septin-6, Glycyl-tRNA synthetase (GARS), Twinfilin-1and eukaryotic elongation factor1-beta(eEF1B); Six proteins for which expression was significantly increased in lysine-treated DCMECswere selected, The6up-regulated expressed phosphoproteins included SKIV2L2、sec-relatedprotein D、T-complex protein1subunit delta、protein disulfide-isomerase A3、coronin actin bindingprotein1C and mitogen-activated protein kinase1(MAPK1); the expression levels of these wereverified by quantitative real-time PCR (qRT-PCR) and western blotting analysis, which wereconsisted with the results of2-DE. In this research, eukaryotic expression vectorpGCMV-IRES-EGFP-MAPK1and pGCMV-IRES-EGFP-eEF1B were constructed by stablytransfected into DCMECs after geneticin (G418) selection. The gene functions of MAPK1andeEF1B were identified by the RNA interference and gene overexpression, methionine and lysine asenergy substrates can promote expression of Stat5a gene and increase lactation of DCMECs byMAPK1and eEF1B. MAPK1and eEF1B also regulates the expression of key mediators of thePRLR/JAK2/STAT5and mTOR signaling pathway. We used Co-immunoprecipitation andGST-pull down assay here to identify the interacting proteins of MAPK1, including ARPC4、β-enolase、Annexin A2、Small G protein signaling modulator1and Polymerase I and transcript release factor, the interacting proteins of eEF1B are14-3-3theta、heat shock protein、eEF1A1、small nuclear ribonucleoprotein polypeptide A and40S ribosomal protein S4.
The results of this research have enriched the study content of nutritional genomics of dairycow, and have important basic theory and research methods.
本研究采用组织块儿培养法，成功构建了体外培养的奶牛乳腺上皮细胞模型，应用CASY细胞分析仪检测了不同浓度和作用时间下蛋氨酸和赖氨酸对奶牛乳腺上皮细胞活力的影响，利用高效液相色谱检测了β-casein的分泌情况，确定了蛋氨酸和赖氨酸最佳剂量分别为0.6mmol/L和1.2mmol/L，最佳作用时间为24h。建立奶牛乳腺上皮细胞核磷酸化蛋白质组技术，应用双向电泳（2-DE）结合质谱技术（MALDI-TOF-MS）鉴定蛋氨酸和赖氨酸对奶牛乳腺上皮细胞核磷酸化蛋白质的差异影响，发现蛋氨酸处理组，Staphylococcal nucleasedomain-containing protein1、Glycyl-tRNA synthetase、Septin-6、Twinfilin-1和Elongationfactor1-beta （eEF1B）蛋白质表达上调，赖氨酸处理组，SKIV2L2、sec-related protein D、T-complex protein1subunit delta、protein disulfide-isomerase A3、coronin actin binding protein1C和mitogen-activated protein kinase1（MAPK1）蛋白质表达上调；并应用荧光定量PCR和Western blotting技术验证差异蛋白在转录水平和蛋白水平上的表达，与2-DE结果一致。实验过程中，采用基因沉寂技术，qRT-PCR鉴定eEF1B（P<0.05）和MAPK1基因沉寂有效（P<0.01），应用Western blotting检测了沉寂eEF1B后，mTOR（P<0.05）、Phospho-mTOR（P<0.05）、GARS（P<0.05）和SND1（P<0.05）蛋白表达降低，并且差异显著，而Stat5（P>0.05）和Phospho-Stat5（P>0.05）蛋白表达稍有降低，但差异不显著；高效液相色谱检测β-酪蛋白含量增加，并且差异显著（P<0.05）。沉寂MAPK1后，mTOR（P<0.05）、Phospho-mTOR（P<0.01）、S6K1（P<0.05）、Phospho-S6K1（P<0.05）、Stat5（P<0.05）和Phospho-Stat5（P<0.05）蛋白表达降低，并且差异显著；高效液相色谱检测β-酪蛋白含量增加，并且差异极其显著（P<0.01）。采用基因过表达技术，qRT-PCR鉴定eEF1B（P<0.01）和MAPK1基因表达增高（P<0.05），应用Western blotting检测了过表达eEF1B后，mTOR（P<0.05）、Phospho-mTOR（P<0.05）、GARS（P<0.05）和SND1（P<0.05）蛋白表达降低，并且差异显著，而Stat5（P>0.05）和Phospho-Stat5（P>0.05）蛋白表达变化不明显；高效液相色谱检测β-酪蛋白含量增加，但差异不显著（P>0.05）。过表达MAPK1后，mTOR（P<0.05）、Phospho-mTOR（P<0.05）、S6K1（P<0.05）和Stat5（P<0.01）蛋白表达升高，并且差异显著；而Phospho-S6K1、Phospho-Stat5蛋白表达升高，但差异不显著（P>0.05）；高效液相色谱检测β-酪蛋白含量增加，并且差异极其显著（P<0.01）。实验过程中通过G418筛选获得稳定转染pGCMV-IRES-EGFP-eEF1B和pGCMV-IRES-EGFP-MAPK1的细胞株，稳定转染细胞后，分别添加蛋氨酸和赖氨酸，应用Western blotting检测了mTOR（P<0.05）和Phospho-mTOR（P<0.05）的表达变化，发现蛋氨酸和赖氨酸营养素可以通过调节MAPK1和eEF1B介导mTOR信号转导通路，进而调节乳蛋白的表达。应用细胞免疫沉淀和GST-pull down技术并联合质谱鉴定与MAPK1相互作用的蛋白有ARPC4、β-enolase、Annexin A2、Small G protein signaling modulator1和PolymeraseI and transcript release factor；与eEF1B相互作用的蛋白有14-3-3theta、Heat shock protein、eEF1A1、Small nuclear ribonucleoprotein polypeptide A和40S ribosomal protein S4。
以上实验结果为奶牛营养基因组学的研究提供了理论依据和技术方法。
China is a country of milk, but milk yield is low, a high incidence of seriously restricting thedevelopment of China's dairy industry, how to improve the milk yield and quality has become anurgent problem. Methionine and lysine are important precursors of milk protein synthesis, previousstudies mainly focused on the effects of methionine and lysine on production performance of dairycows, while the effects of lactation regulation on dairy cow mammary gland epithelial cells(DCMECs) are poorly researched. In order to determine genes of milk protein synthesis in dairycows and reveal the mechanism of important functional genes in milk protein synthesis haveimportant basic theory and research methods by regulating mammary gland development.
A dairy cow mammary epithelial cell line was established through culture method of tissueblock and detection of cell biological characters. Effects of methionine and lysine on viabilitiesand β-casein of DCMECs were evaluated by CASY and HPLC, and determined the optimal dose ofmethionine and lysine was0.6mmol/L and1.2mmol/L, the best time was24h. A nuclearphosphoproteomics of DCMECs was successfully established, five proteins for which expressionwas significantly increased in methionine-treated DCMECs were selected, the5up-regulatedexpressed phosphoproteins included staphylococcal nuclease domain-containing protein1(SND1),Septin-6, Glycyl-tRNA synthetase (GARS), Twinfilin-1and eukaryotic elongation factor1-beta(eEF1B); Six proteins for which expression was significantly increased in lysine-treated DCMECswere selected, The6up-regulated expressed phosphoproteins included SKIV2L2、sec-relatedprotein D、T-complex protein1subunit delta、protein disulfide-isomerase A3、coronin actin bindingprotein1C and mitogen-activated protein kinase1(MAPK1); the expression levels of these wereverified by quantitative real-time PCR (qRT-PCR) and western blotting analysis, which wereconsisted with the results of2-DE. In this research, eukaryotic expression vectorpGCMV-IRES-EGFP-MAPK1and pGCMV-IRES-EGFP-eEF1B were constructed by stablytransfected into DCMECs after geneticin (G418) selection. The gene functions of MAPK1andeEF1B were identified by the RNA interference and gene overexpression, methionine and lysine asenergy substrates can promote expression of Stat5a gene and increase lactation of DCMECs byMAPK1and eEF1B. MAPK1and eEF1B also regulates the expression of key mediators of thePRLR/JAK2/STAT5and mTOR signaling pathway. We used Co-immunoprecipitation andGST-pull down assay here to identify the interacting proteins of MAPK1, including ARPC4、β-enolase、Annexin A2、Small G protein signaling modulator1and Polymerase I and transcript release factor, the interacting proteins of eEF1B are14-3-3theta、heat shock protein、eEF1A1、small nuclear ribonucleoprotein polypeptide A and40S ribosomal protein S4.
The results of this research have enriched the study content of nutritional genomics of dairycow, and have important basic theory and research methods.
引文
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