血管生成素与磷脂混杂酶1相互作用及其功能研究
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摘要
血管生成素(Angiogenin,ANG)能够促进血管新生和肿瘤增殖,然而作用机制未明。由于蛋白质相互作用在生命活动中扮演关键角色,研究ANG相互作用蛋白质将是阐明其作用机制的有效途径。
酵母双杂交技术是目前被普遍采用的高通量筛选相互作用蛋白质的方法之一。在前期工作中,本实验室已经成功地用酵母双杂交法从人心肌cDNA文库筛选到22个与ANG存在相互作用的蛋白质。考虑到肝脏是ANG的主要合成脏器,也为了发现更多的ANG相互作用蛋白质,本论文再次利用酵母双杂交方法对人肝cDNA文库进行了筛选,并获得了8个能够与ANG在酵母细胞中发生相互作用的蛋白质,其中有4个与从心肌cDNA文库中筛选到的蛋白质一致。这些与血管生成素有潜在相互作用的新蛋白的发现,扩充了实验室前期发现的血管生成素相互作用蛋白数据库,为探索血管生成素作用机制提供了新的线索。
磷脂混杂酶1(phospholipid scramblase 1,PLSCR1)是此次筛选到的ANG相互作用蛋白之一。它是一个Ⅱ型膜蛋白,最初因其磷脂混杂酶活性而得名。近年来的研究发现PLSCR1能够转位到细胞核内,但其在细胞核内行使的生物学功能尚不明确。
酵母双杂交系统显示的相互作用蛋白还需要利用其它研究蛋白质相互作用的方法进一步验证。因此,我们首先采用体外GST沉降(GST-pull down)以及体内免疫共沉淀(co-immunoprecipitation)技术证明了PLSCR1与ANG相互作用的真实性。为了进一步了解PLSCR1在细胞内的定位以及与ANG的共定位情况,我们用荧光蛋白CFP和YFP分别标记PLSCR1和ANG,通过转染方法在HeLa细胞内实现高表达后,用激光共聚焦显微镜进行观察。结果显示,融合蛋白CFP-PLSCR1和YFP-ANG明显地共定位于细胞核。经FRET分析证实,两者能够在细胞核内发生相互作用。此外,为排除标签蛋白CFP和YFP对目标蛋白定位的影响,我们采用间接免疫荧光方法以及细胞核免疫共沉淀的方法检测到不带荧光蛋白标签的PLSCR1与ANG也能够在细胞核内共定位并发生相互作用。
已知细胞核内的ANG具有促进rRNA转录的活性;ANG的核转位及其促rRNA转录活性是ANG诱导细胞增殖和血管新生的基础。然而到目前为止,ANG在细胞核内促进rRNA转录以及调节ANG促rRNA转录过程的分子机制均未明了。基于PLSCR1能够与ANG在细胞核内发生相互作用,我们进一步检测了PLSCR1对ANG促进的rRNA转录活性的影响。结果显示,在HeLa细胞内,PLSCR1水平与rRNA的转录水平呈正相关,且过表达PLSCR1引起的rRNA转录活性增加必须依赖于细胞内ANG的存在。因而,我们认为PLSCR1能够增强ANG促进的rRNA转录活性。
基于以上研究结果,我们得出如下结论:
1.颗粒蛋白(granulin,GRN)、纤黏连蛋白1(fibronectin 1,FN 1)、内质网降解途径相关的泛素连接酶HRD1(ERAD-associated E3 ubiquitin-protein ligaseHRD1)、血管内皮紧张素(vascular endothelial statin,VE-statin)、潜在型TGF-β结合蛋白3(latent transforming growth factor beta binding protein 3,LTBP3)、磷脂混杂酶1、Sprouty1(Spry1)和脊索蛋白(chordin,CHRD)等是用酵母双杂交技术从人肝cDNA文库中筛选到的8种潜在的ANG相互作用蛋白质。
2.PLSCR1是ANG在HeLa细胞中的相互作用蛋白质。
3.PLSCR1与ANG的相互作用可以发生在HeLa细胞的细胞核内。
4.在HeLa细胞内,PLSCR1可以正向调节ANG促进的rRNA转录。
Angiogenin(ANG) potentiates angiogenesis and tumor cell proliferation.However, the underlied molecular mechanisms remain elusive.Since the protein-protein interaction plays essential role in the biological events,exploring the ANG-interacted proteins could be an effective pathway to elucidate those ANG-mediated processes.
Yeast two-hybrid screen is one of the widely used methods to search for unknown interacting proteins.Taking ANG as the bait,the original fellowers had successfully screened a human heart cDNA library in the yeast two-hybrid system,and indentified several ANG-interacted proteins.In order to find out more ANG-interacted molecules, here we continue to carry out the yeast two-hybrid screen with a human liver cDNA library.8 potential ANG-interacted proteins were identified,4 of which had also been identified from the human heart cDNA library screen.These newly identified ANG-interacted proteins could help us to further understand the molecular mechanisms of ANG.
Phospholipid scramblase 1(PLSCR1) is one of the novel identified ANG-interacted proteins.It is an endofacial membrane protein and named after its phospholipid scramblase activity.More recently,PLSCR1 was found to translocate into the nuclei under certain conditions,though its nuclear function remains unclear.
The interactions identified from yeast two-hybrid screen may be false positive. Therefore,the interaction between PLSCR1 and ANG need to be confirmed by other methods.The results from GST pull-down and in vivo co-immunoprecipitaion assays revealed that these two proteins did interact with each other both in vitro and in vivo. Thereafter,the endocellular co-localization and interaction of PLSCR1 and ANG was further explored.When ectopically expressed in HeLa cells,the flurescent protein-tagged PLSCR1(CFP-tagged) and ANG(YFP-tagged) were found to co-localize and physically interact with each other in the nuclei.The nuclear interaction was also observed from the HA-tagged PLSCR1 and native ANG by using indirect immunoflurence detection and nuclear coimmunoprecipitaiton analysis.These results revealed that PLSCR1 and ANG interact in the nuclei of HeLa cells.
The nuclear localized ANG could promote the rRNA transcription,a process thought to be essential for ANG to exert its angiogenic and tumorigenic activites. However,the mechanism and regulation of ANG-enhancing rRNA transcription remain elusive.As a physical nuclear interacting partner of ANG,PLSCR1 was then explored for its influence on ANG-mediated rRNA transcription.We found that the PLSCR1 protein level was positively correlated with the rRNA transcription activity in HeLa cells;and moreover,PLSCR1 enhanced the rRNA transcription level only when ANG was available.The current data thus demonstrated that PLSCR1 could positively regulate the ANG-enhancing rRNA transcription at least in HeLa cells.
Therefore,innovative conclusions could be drawn base on the data:
1.Granulin(GRN),Fibronectinl(FN1),ERAD-associated E3 ubiquitin-protein ligase HRD1(HRD1),vascular endothelial statin(VE-statin),latent transforming growth factor beta binding protein 3(LTBP3),PLSCR1,Sprouty1(Spry1) and chordin(CHRD) are 8 potential ANG-interacted proteins indentified from the yeast two-hybrid screen with a human liver cDNA library as the prey.
2.PLSCR1 could directly interact with ANG in HeLa cells.
3.The interaction between PLSCR1 and ANG could take place in the nuclei of HeLa cells.
4.PLSCR1 could upregulate the ANG-enhancing rRNA transcription in HeLa cells.
酵母双杂交技术是目前被普遍采用的高通量筛选相互作用蛋白质的方法之一。在前期工作中,本实验室已经成功地用酵母双杂交法从人心肌cDNA文库筛选到22个与ANG存在相互作用的蛋白质。考虑到肝脏是ANG的主要合成脏器,也为了发现更多的ANG相互作用蛋白质,本论文再次利用酵母双杂交方法对人肝cDNA文库进行了筛选,并获得了8个能够与ANG在酵母细胞中发生相互作用的蛋白质,其中有4个与从心肌cDNA文库中筛选到的蛋白质一致。这些与血管生成素有潜在相互作用的新蛋白的发现,扩充了实验室前期发现的血管生成素相互作用蛋白数据库,为探索血管生成素作用机制提供了新的线索。
磷脂混杂酶1(phospholipid scramblase 1,PLSCR1)是此次筛选到的ANG相互作用蛋白之一。它是一个Ⅱ型膜蛋白,最初因其磷脂混杂酶活性而得名。近年来的研究发现PLSCR1能够转位到细胞核内,但其在细胞核内行使的生物学功能尚不明确。
酵母双杂交系统显示的相互作用蛋白还需要利用其它研究蛋白质相互作用的方法进一步验证。因此,我们首先采用体外GST沉降(GST-pull down)以及体内免疫共沉淀(co-immunoprecipitation)技术证明了PLSCR1与ANG相互作用的真实性。为了进一步了解PLSCR1在细胞内的定位以及与ANG的共定位情况,我们用荧光蛋白CFP和YFP分别标记PLSCR1和ANG,通过转染方法在HeLa细胞内实现高表达后,用激光共聚焦显微镜进行观察。结果显示,融合蛋白CFP-PLSCR1和YFP-ANG明显地共定位于细胞核。经FRET分析证实,两者能够在细胞核内发生相互作用。此外,为排除标签蛋白CFP和YFP对目标蛋白定位的影响,我们采用间接免疫荧光方法以及细胞核免疫共沉淀的方法检测到不带荧光蛋白标签的PLSCR1与ANG也能够在细胞核内共定位并发生相互作用。
已知细胞核内的ANG具有促进rRNA转录的活性;ANG的核转位及其促rRNA转录活性是ANG诱导细胞增殖和血管新生的基础。然而到目前为止,ANG在细胞核内促进rRNA转录以及调节ANG促rRNA转录过程的分子机制均未明了。基于PLSCR1能够与ANG在细胞核内发生相互作用,我们进一步检测了PLSCR1对ANG促进的rRNA转录活性的影响。结果显示,在HeLa细胞内,PLSCR1水平与rRNA的转录水平呈正相关,且过表达PLSCR1引起的rRNA转录活性增加必须依赖于细胞内ANG的存在。因而,我们认为PLSCR1能够增强ANG促进的rRNA转录活性。
基于以上研究结果,我们得出如下结论:
1.颗粒蛋白(granulin,GRN)、纤黏连蛋白1(fibronectin 1,FN 1)、内质网降解途径相关的泛素连接酶HRD1(ERAD-associated E3 ubiquitin-protein ligaseHRD1)、血管内皮紧张素(vascular endothelial statin,VE-statin)、潜在型TGF-β结合蛋白3(latent transforming growth factor beta binding protein 3,LTBP3)、磷脂混杂酶1、Sprouty1(Spry1)和脊索蛋白(chordin,CHRD)等是用酵母双杂交技术从人肝cDNA文库中筛选到的8种潜在的ANG相互作用蛋白质。
2.PLSCR1是ANG在HeLa细胞中的相互作用蛋白质。
3.PLSCR1与ANG的相互作用可以发生在HeLa细胞的细胞核内。
4.在HeLa细胞内,PLSCR1可以正向调节ANG促进的rRNA转录。
Angiogenin(ANG) potentiates angiogenesis and tumor cell proliferation.However, the underlied molecular mechanisms remain elusive.Since the protein-protein interaction plays essential role in the biological events,exploring the ANG-interacted proteins could be an effective pathway to elucidate those ANG-mediated processes.
Yeast two-hybrid screen is one of the widely used methods to search for unknown interacting proteins.Taking ANG as the bait,the original fellowers had successfully screened a human heart cDNA library in the yeast two-hybrid system,and indentified several ANG-interacted proteins.In order to find out more ANG-interacted molecules, here we continue to carry out the yeast two-hybrid screen with a human liver cDNA library.8 potential ANG-interacted proteins were identified,4 of which had also been identified from the human heart cDNA library screen.These newly identified ANG-interacted proteins could help us to further understand the molecular mechanisms of ANG.
Phospholipid scramblase 1(PLSCR1) is one of the novel identified ANG-interacted proteins.It is an endofacial membrane protein and named after its phospholipid scramblase activity.More recently,PLSCR1 was found to translocate into the nuclei under certain conditions,though its nuclear function remains unclear.
The interactions identified from yeast two-hybrid screen may be false positive. Therefore,the interaction between PLSCR1 and ANG need to be confirmed by other methods.The results from GST pull-down and in vivo co-immunoprecipitaion assays revealed that these two proteins did interact with each other both in vitro and in vivo. Thereafter,the endocellular co-localization and interaction of PLSCR1 and ANG was further explored.When ectopically expressed in HeLa cells,the flurescent protein-tagged PLSCR1(CFP-tagged) and ANG(YFP-tagged) were found to co-localize and physically interact with each other in the nuclei.The nuclear interaction was also observed from the HA-tagged PLSCR1 and native ANG by using indirect immunoflurence detection and nuclear coimmunoprecipitaiton analysis.These results revealed that PLSCR1 and ANG interact in the nuclei of HeLa cells.
The nuclear localized ANG could promote the rRNA transcription,a process thought to be essential for ANG to exert its angiogenic and tumorigenic activites. However,the mechanism and regulation of ANG-enhancing rRNA transcription remain elusive.As a physical nuclear interacting partner of ANG,PLSCR1 was then explored for its influence on ANG-mediated rRNA transcription.We found that the PLSCR1 protein level was positively correlated with the rRNA transcription activity in HeLa cells;and moreover,PLSCR1 enhanced the rRNA transcription level only when ANG was available.The current data thus demonstrated that PLSCR1 could positively regulate the ANG-enhancing rRNA transcription at least in HeLa cells.
Therefore,innovative conclusions could be drawn base on the data:
1.Granulin(GRN),Fibronectinl(FN1),ERAD-associated E3 ubiquitin-protein ligase HRD1(HRD1),vascular endothelial statin(VE-statin),latent transforming growth factor beta binding protein 3(LTBP3),PLSCR1,Sprouty1(Spry1) and chordin(CHRD) are 8 potential ANG-interacted proteins indentified from the yeast two-hybrid screen with a human liver cDNA library as the prey.
2.PLSCR1 could directly interact with ANG in HeLa cells.
3.The interaction between PLSCR1 and ANG could take place in the nuclei of HeLa cells.
4.PLSCR1 could upregulate the ANG-enhancing rRNA transcription in HeLa cells.
引文
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13.Nanjundan,M.,et al.,Plasma membrane phospholipid scramblase 1 promotes EGF-dependent activation of c-Src through the epidermal growth factor receptor.J Biol Chem,2003.278(39):p.37413-8.
14.Kametaka,S.,et al.,Identification of phospholipid scramblase 1 as a novel interacting molecule with beta-secretase (beta-site amyloid precursor protein (APP)cleaving enzyme (BACE)).J Biol Chem,2003.278(17):p.15239-45.
15.Li,Y.,et al.,The negative c-Myc target onzin affects proliferation and apoptosis via its obligate interaction with phospholipid scramblase 1.Mol Cell Biol,2006.26(9):p.3401-13.
16.Frasch,S.C.,et al.,Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase Cdelta.J Biol Chem,2000.275(30):p.23065-73.
17.Pastorelli,C,et al.,IgE receptor type I-dependent tyrosine phosphorylation of phospholipid scramblase.J Biol Chem,2001.276(23):p.20407-12.
18.Chen,M.H.,et al.,Phospholipid scramblase 1 contains a nonclassical nuclear localization signal with unique binding site in importin alpha J Biol Chem,2005.280(11):p.10599-606.
19.Ben-Efraim,I.,et al.,Phospholipid scramblase 1 is imported into the nucleus by a receptor-mediated pathway and interacts with DNA.Biochemistry,2004.43(12):p.3518-26.
20.Zhou,Q.,et al.,Phospholipid scramblase 1 binds to the promoter region of the inositol 1,4,5-triphosphate receptor type 1 gene to enhance its expression.J Biol Chem,2005.280(41):p.35062-8.
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24.Huang,Y.,et al.,Antileukemic roles of human phospholipid scramblase 1 gene,evidence from inducible PLSCR1-expressing leukemic cells.Oncogene,2006.25(50):p.6618-27.
25.Zhang,K.,et al.,Wogonin induces the granulocytic differentiation of human NB4 promyelocyte leukemia cells and up-regulates phospholipid scramblase 1 gene expression.Cancer Sci,2008.99(4):p.689-95.
26.Kasukabe,T.,J.Okabe-Kado,and Y.Honma,TRA1,a novel mRNA highly expressed in leukemogenic mouse monocytic sublines but not in nonleukemogenic sublines.Blood,1997.89(8):p.2975-85.
27.Yu,A.,et al.,Stimulation of phosphatidylserine biosynthesis and facilitation of UV-induced apoptosis in Chinese hamster ovary cells overexpressing phospholipid scramblase 1.J Biol Chem,2003.278(11):p.9706-14.
28.Silverman,R.H.,et al.,Suppression of ovarian carcinoma cell growth in vivo by the interferon-inducible plasma membrane protein,phospholipid scramblase 1.Cancer Res,2002.62(2):p.397-402.
29.Huang,Y,Q.Zhao,and GQ.Chen,Phospholipid scramblase 1.Sheng Li Xue Bao,2006.58(6):p.501-510.
30.Dong,B.,et al.,Phospholipid scramblase 1 potentiates the antiviral activity of interferon.J Virol,2004.78(17):p.8983-93.
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6.Zhou,Q.,et al.,Transcriptional control of the human plasma membrane phospholipid scramblase 1 gene is mediated by interferon-alpha.Blood,2000.95(8):p.2593-9.
7.Zhao,K.W.,et al.,Interferon-alpha-induced expression of phospholipid scramblase 1 through STAT1 requires the sequential activation of protein kinase Cdelta and JNK.J Biol Chem,2005.280(52):p.42707-14.
8.Lu,B.,et al.,Expression of the phospholipid scramblase (PLSCR)gene family during the acute phase response.Biochim Biophys Acta,2007.1771(9):p.1177-85.
9.Zhao,K.W.,et al.,Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression:its role in leukemic cell differentiation.Blood,2004.104(12):p.3731-8.
10.Zhou,Q.,et al.,Normal hemostasis but defective hematopoietic response to growth factors in mice deficient in phospholipid scramblase 1.Blood,2002.99(11):p.4030-8.
11.Sun,J.,et al.,Plasma membrane phospholipid scramblase 1 is enriched in lipid rafts and interacts with the epidermal growth factor receptor.Biochemistry,2002. 41(20):p.6338-45.
12.Yokoyama,A.,et al.,MmTRAlb/phospholipid scramblase 1 gene expression is a new prognostic factor for acute myelogenous leukemia Leuk Res,2004.28(2):p.149-57.
13.Nanjundan,M.,et al.,Plasma membrane phospholipid scramblase 1 promotes EGF-dependent activation of c-Src through the epidermal growth factor receptor.J Biol Chem,2003.278(39):p.37413-8.
14.Kametaka,S.,et al.,Identification of phospholipid scramblase 1 as a novel interacting molecule with beta-secretase (beta-site amyloid precursor protein (APP)cleaving enzyme (BACE)).J Biol Chem,2003.278(17):p.15239-45.
15.Li,Y.,et al.,The negative c-Myc target onzin affects proliferation and apoptosis via its obligate interaction with phospholipid scramblase 1.Mol Cell Biol,2006.26(9):p.3401-13.
16.Frasch,S.C.,et al.,Regulation of phospholipid scramblase activity during apoptosis and cell activation by protein kinase Cdelta.J Biol Chem,2000.275(30):p.23065-73.
17.Pastorelli,C,et al.,IgE receptor type I-dependent tyrosine phosphorylation of phospholipid scramblase.J Biol Chem,2001.276(23):p.20407-12.
18.Chen,M.H.,et al.,Phospholipid scramblase 1 contains a nonclassical nuclear localization signal with unique binding site in importin alpha J Biol Chem,2005.280(11):p.10599-606.
19.Ben-Efraim,I.,et al.,Phospholipid scramblase 1 is imported into the nucleus by a receptor-mediated pathway and interacts with DNA.Biochemistry,2004.43(12):p.3518-26.
20.Zhou,Q.,et al.,Phospholipid scramblase 1 binds to the promoter region of the inositol 1,4,5-triphosphate receptor type 1 gene to enhance its expression.J Biol Chem,2005.280(41):p.35062-8.
21.Wyles,J.P.,et al.,Nuclear interactions of topoisomerase Ⅱ alpha and beta with phospholipid scramblase 1.Nucleic Acids Res,2007.35(12):p.4076-85.
22.Comfurius,P.,et al.,Reconstitution of phospholipid scramblase activity from human blood platelets.Biochemistry,1996.35(24):p.7631-4.
23.Zhou,Q.,P.J.Sims,and T.Wiedmer,Expression of proteins controlling transbilayer movement of plasma membrane phospholipids in the B lymphocytes from a patient with Scott syndrome.Blood,1998.92(5):p.1707-12.
24.Huang,Y.,et al.,Antileukemic roles of human phospholipid scramblase 1 gene,evidence from inducible PLSCR1-expressing leukemic cells.Oncogene,2006.25(50):p.6618-27.
25.Zhang,K.,et al.,Wogonin induces the granulocytic differentiation of human NB4 promyelocyte leukemia cells and up-regulates phospholipid scramblase 1 gene expression.Cancer Sci,2008.99(4):p.689-95.
26.Kasukabe,T.,J.Okabe-Kado,and Y.Honma,TRA1,a novel mRNA highly expressed in leukemogenic mouse monocytic sublines but not in nonleukemogenic sublines.Blood,1997.89(8):p.2975-85.
27.Yu,A.,et al.,Stimulation of phosphatidylserine biosynthesis and facilitation of UV-induced apoptosis in Chinese hamster ovary cells overexpressing phospholipid scramblase 1.J Biol Chem,2003.278(11):p.9706-14.
28.Silverman,R.H.,et al.,Suppression of ovarian carcinoma cell growth in vivo by the interferon-inducible plasma membrane protein,phospholipid scramblase 1.Cancer Res,2002.62(2):p.397-402.
29.Huang,Y,Q.Zhao,and GQ.Chen,Phospholipid scramblase 1.Sheng Li Xue Bao,2006.58(6):p.501-510.
30.Dong,B.,et al.,Phospholipid scramblase 1 potentiates the antiviral activity of interferon.J Virol,2004.78(17):p.8983-93.
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2.Alberts,B.,Molecular Biology of the Cell,ed.3rd.1994.
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