颗粒蛋白前体与血管生成素相互作用及其功能研究
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摘要
血管生成素(angiogenin，ANG)是一个强有力的促血管生成因子，并可直接作用于肿瘤细胞。临床调查表明它与肿瘤的发生、发展密切相关。但目前对血管生成素诱导血管生成和肿瘤发生的分子机制的认识还不全面，许多方面尚待进一步研究。
基于蛋白质相互作用在生命活动中扮演的重要角色，我们推测蛋白质的相互作用必定介导或调节了血管生成素促进的肿瘤血管生成及肿瘤细胞增殖等生物学过程。为全面探索血管生成素功能活动中的蛋白质相互作用情况，本实验室曾用酵母双杂交技术从人心肌和肝cDNA文库筛选获得了一批与血管生成素可能有相互作用的候选蛋白质，颗粒蛋白前体(Progranulin，PGRN)即为其中的一员。由于颗粒蛋白前体在调节生长发育、损伤修复和促进细胞增殖以及促进血管生成等方面均发挥重要功能，本论文对血管生成素与颗粒蛋白前体的相互作用及意义进行了研究。
首先，我们利用研究蛋白质相互作用的体内外方法证实了血管生成素与颗粒蛋白前体的相互作用。在确证血管生成素可以在酵母细胞中与颗粒蛋白前体相互作用的基础上，我们利用体外免疫共沉淀证明它们在体外有直接的结合。然后，在HeLa细胞中分别表达了CFP-PGRN和YFP-ANG，激光共聚焦显微镜下观察它们在细胞内的定位情况。结果显示，CFP-PGRN单独表达时主要存在于细胞质中，YFP-ANG单独表达时均匀分布于细胞核内，但两种蛋白共同表达后，血管生成素的分布情况发生了变化，从核内转移到了细胞质内，并与颗粒蛋白前体有细胞质共定位。当在HeLa细胞中过量表达颗粒蛋白前体时，胞外血管生成素的核转位被阻断。荧光共振能量转移(FRET)分析也证实了血管生成素与颗粒蛋白前体在HeLa细胞内的相互作用。
在确证颗粒蛋白前体与血管生成素的相互作用后，我们进一步用酵母双杂交法研究了颗粒蛋白前体中与血管生成素的作用位点。结果表明，颗粒蛋白前体的N-端grnPGF或C-端grnDE两个结构域均可以与血管生成素相结合。这种相互作用也得到了体内FRET实验和体外GST pull-down实验结果的证实。同时，我们也用酵母双杂交技术对血管生成素内与颗粒蛋白前体作用的结合位点或关键氨基酸进行了探索。实验结果显示，血管生成素内与颗粒蛋白前体结合的最小片段为第63-110位氨基酸，没有发现与颗粒蛋白前体相互作用的关键氨基酸。
为探索颗粒蛋白前体及其衍生物与血管生成素相互作用的生物学意义，我们利用荧光素酶报告系统分析了它们对血管生成素促进的ABE启动子活性的影响。结果表明，ABE序列在验证启动子活性的质粒pGL3E中表现出启动子活性；血管生成素可以促进ABE启动子活性；颗粒蛋白前体的表达对ABE的启动子活性没有影响；但颗粒蛋白前体与血管生成素相互作用能抑制血管生成素对ABE启动子的促转录活性。同时，grnPGF和grnDE两个结构域也都能抑制血管生成素对ABE启动子的促转录活性。这些结果表明颗粒蛋白前体及其衍生物可以调节血管生成素的生物学活性。
基于以上研究结果，我们得出如下结论：
1．颗粒蛋白前体是血管生成素的相互作用蛋白质。
2．颗粒蛋白前体的grnPGF或grnDE结构域介导其与血管生成素的相互作用。
3．血管生成素通过其63-110之间的氨基酸与颗粒蛋白前体相互作用。
4．颗粒蛋白前体及其衍生物N-端结构域grnPGF或C-端结构域grnDE是血管生成素的调节因子。
Angiogenin is a potent angiogenic growth factor, originally isolated from theconditioned medium of HT-29 human colon adenocarcinoma cells. Elevated serumangiogenin levels in many types of cancers suggest that it is closely related to tumorgrowth, progression and metastasis. Recently, angiogenin was found to directly act ontumor cells and promote proliferation. However, the molecular mechanismsunderlying the functions of angiogenin remain elusive.
Since protein interactions are critical in every biological process, we reason thatinteractions between angiogenin and other proteins should mediate a series of cellularevents in angiogenesis and tumor cell growth. But until now only a few proteins havebeen identified as angiogenin interacting partners, which is not enough to clarify themolecular mechanism of ANG-induced angiogenesis and tumorigenesis.
To identify additional mediators or modulators of angiogenin, we have carried out ayeast two-hybrid screening and identified progranulin, which is an autocrine growthfactor and plays an important role in tube formation, wound repair, and tumor cellproliferation, as a potential angiogenin-binding protein. In this thesis, we carried outfurther studies to confirm the interactions between progranulin and angiogenin, andthen explore the biological implication of the interaction.
After reassuring progranulin did interact with angiogenin in yeast cells, weconfirmed it by an in vitro co-immunoprecipitation experiment. First the progranulinwas expressed in an in vitro TNT~(?) T7 expression system and labeled with ~(35)[S]-Met.Then angiogenin was incubated with the in vitro expressed products, andco-immunoprecipitated by anti-angiogenin antibody. The pellets were subjected to SDS-PAGE and then autoradiography. The results showed that progranulin wasco-immunoprecipitated with angiogenin, indicating that there is direct interactionbetween progranulin and angiogenin.
To document if there is a specific interaction between progranulin and angiogeninin living cells, we firstly examined their intracellular localization. The images of theCFP-tagged progranulin and/or YFP-tagged angiogenin were monitored by a confocalmicroscope. Data revealed that single transfection of progranulin into HeLa cellsshowed a predominant distribution in the cytoplasm; Angiogenin was present mainlyin the nucleus. When the two proteins were co-expressed in HeLa cells, however, thedistribution pattern of angiogenin was altered: it moved into the cytoplasm andco-localized with the progranulin. When exogenous angiogenin was applied to theculture media of HeLa cells pre-transfected with progranulin, its nuclear translocationwas blocked. These data provide evidence to reveal that progranulin interacts withangiogenin in a living cell. Then, we further confirmed their interactions in thecytoplasm using fluorescence resonance energy transfer (FRET) methodology.
To narrow down the binding domain with ANG in progranulin, we constructed aseries of truncated fragments of progranulin into vector pEXP-AD502 and evaluatedtheir interactions with angiogenin in yeast cells. Data showed that either theN-terminal PGF domain or C-terminal DE domain interacted with angiogenin,indicating that binding of angiogenin requires at least two tandem domains. Thefollowing FRET analysis and GST pull-down assay further confirmed the interactionsbetween grnPGF or grnDE with angiogenin. Meanwhile, the binding sites and keyamino acids in angiogenin were explored. The results showed that the smallestfragment binding to progranulin in angiogenin was from amino acid 63 to 110, but nokey amino acids were detected.
We were then curious about the biological consequences of the interaction betweenangiogenin and progranulin. Based on the fact that progranulin inhibits angiogeinnuclear translocation, we speculated that progranulin or its binding domains mayregulate angiogenin's nuclear function. To test that hypothesis, an ABE-luciferasereporter system was applied. The results showed that the expression level of luciferase in HeLa cells transfected with pGL3E-ABE was nearly 30 times higher than thosetransfected with pGL3E vector, indicating ABE acted as a promoter. Whenco-transfected with angiogenin-expressing plasmid, the activity of luciferaseincreased greatly, indicating that ABE's promoter activity was ANG-dependent.Progranulin had no effect on ABE's promotor activity, as the luciferase expressionlevel did not change much in progranulin co-transfection group. When the cells wereco-transfected with both angiogenin and progranulin, the ABE activity reduced to thebasic level, indicating that progranulin inhibited angiogenin's ABE-driven activity.Correspondingly, grnPGF and grnDE both inhibited angiogenin's ABE-drivenactivity. All these evidence suggested that progranulin or its domains may play as anangiogenin regulator.
Therefore, innovative conclusions could be drawn based on the data:
1. Progranulin is one of the angiogenin-interacting proteins.
2. Either grnPGF or grnDE is responsible for angiogenin binding.
3. The smallest fragment interacting with progranulin in angiogenin is from aminoacid 63 to 110.
4. Progranulin, grnPGF or grnDE is a functional regulator of angiogenin.
基于蛋白质相互作用在生命活动中扮演的重要角色，我们推测蛋白质的相互作用必定介导或调节了血管生成素促进的肿瘤血管生成及肿瘤细胞增殖等生物学过程。为全面探索血管生成素功能活动中的蛋白质相互作用情况，本实验室曾用酵母双杂交技术从人心肌和肝cDNA文库筛选获得了一批与血管生成素可能有相互作用的候选蛋白质，颗粒蛋白前体(Progranulin，PGRN)即为其中的一员。由于颗粒蛋白前体在调节生长发育、损伤修复和促进细胞增殖以及促进血管生成等方面均发挥重要功能，本论文对血管生成素与颗粒蛋白前体的相互作用及意义进行了研究。
首先，我们利用研究蛋白质相互作用的体内外方法证实了血管生成素与颗粒蛋白前体的相互作用。在确证血管生成素可以在酵母细胞中与颗粒蛋白前体相互作用的基础上，我们利用体外免疫共沉淀证明它们在体外有直接的结合。然后，在HeLa细胞中分别表达了CFP-PGRN和YFP-ANG，激光共聚焦显微镜下观察它们在细胞内的定位情况。结果显示，CFP-PGRN单独表达时主要存在于细胞质中，YFP-ANG单独表达时均匀分布于细胞核内，但两种蛋白共同表达后，血管生成素的分布情况发生了变化，从核内转移到了细胞质内，并与颗粒蛋白前体有细胞质共定位。当在HeLa细胞中过量表达颗粒蛋白前体时，胞外血管生成素的核转位被阻断。荧光共振能量转移(FRET)分析也证实了血管生成素与颗粒蛋白前体在HeLa细胞内的相互作用。
在确证颗粒蛋白前体与血管生成素的相互作用后，我们进一步用酵母双杂交法研究了颗粒蛋白前体中与血管生成素的作用位点。结果表明，颗粒蛋白前体的N-端grnPGF或C-端grnDE两个结构域均可以与血管生成素相结合。这种相互作用也得到了体内FRET实验和体外GST pull-down实验结果的证实。同时，我们也用酵母双杂交技术对血管生成素内与颗粒蛋白前体作用的结合位点或关键氨基酸进行了探索。实验结果显示，血管生成素内与颗粒蛋白前体结合的最小片段为第63-110位氨基酸，没有发现与颗粒蛋白前体相互作用的关键氨基酸。
为探索颗粒蛋白前体及其衍生物与血管生成素相互作用的生物学意义，我们利用荧光素酶报告系统分析了它们对血管生成素促进的ABE启动子活性的影响。结果表明，ABE序列在验证启动子活性的质粒pGL3E中表现出启动子活性；血管生成素可以促进ABE启动子活性；颗粒蛋白前体的表达对ABE的启动子活性没有影响；但颗粒蛋白前体与血管生成素相互作用能抑制血管生成素对ABE启动子的促转录活性。同时，grnPGF和grnDE两个结构域也都能抑制血管生成素对ABE启动子的促转录活性。这些结果表明颗粒蛋白前体及其衍生物可以调节血管生成素的生物学活性。
基于以上研究结果，我们得出如下结论：
1．颗粒蛋白前体是血管生成素的相互作用蛋白质。
2．颗粒蛋白前体的grnPGF或grnDE结构域介导其与血管生成素的相互作用。
3．血管生成素通过其63-110之间的氨基酸与颗粒蛋白前体相互作用。
4．颗粒蛋白前体及其衍生物N-端结构域grnPGF或C-端结构域grnDE是血管生成素的调节因子。
Angiogenin is a potent angiogenic growth factor, originally isolated from theconditioned medium of HT-29 human colon adenocarcinoma cells. Elevated serumangiogenin levels in many types of cancers suggest that it is closely related to tumorgrowth, progression and metastasis. Recently, angiogenin was found to directly act ontumor cells and promote proliferation. However, the molecular mechanismsunderlying the functions of angiogenin remain elusive.
Since protein interactions are critical in every biological process, we reason thatinteractions between angiogenin and other proteins should mediate a series of cellularevents in angiogenesis and tumor cell growth. But until now only a few proteins havebeen identified as angiogenin interacting partners, which is not enough to clarify themolecular mechanism of ANG-induced angiogenesis and tumorigenesis.
To identify additional mediators or modulators of angiogenin, we have carried out ayeast two-hybrid screening and identified progranulin, which is an autocrine growthfactor and plays an important role in tube formation, wound repair, and tumor cellproliferation, as a potential angiogenin-binding protein. In this thesis, we carried outfurther studies to confirm the interactions between progranulin and angiogenin, andthen explore the biological implication of the interaction.
After reassuring progranulin did interact with angiogenin in yeast cells, weconfirmed it by an in vitro co-immunoprecipitation experiment. First the progranulinwas expressed in an in vitro TNT~(?) T7 expression system and labeled with ~(35)[S]-Met.Then angiogenin was incubated with the in vitro expressed products, andco-immunoprecipitated by anti-angiogenin antibody. The pellets were subjected to SDS-PAGE and then autoradiography. The results showed that progranulin wasco-immunoprecipitated with angiogenin, indicating that there is direct interactionbetween progranulin and angiogenin.
To document if there is a specific interaction between progranulin and angiogeninin living cells, we firstly examined their intracellular localization. The images of theCFP-tagged progranulin and/or YFP-tagged angiogenin were monitored by a confocalmicroscope. Data revealed that single transfection of progranulin into HeLa cellsshowed a predominant distribution in the cytoplasm; Angiogenin was present mainlyin the nucleus. When the two proteins were co-expressed in HeLa cells, however, thedistribution pattern of angiogenin was altered: it moved into the cytoplasm andco-localized with the progranulin. When exogenous angiogenin was applied to theculture media of HeLa cells pre-transfected with progranulin, its nuclear translocationwas blocked. These data provide evidence to reveal that progranulin interacts withangiogenin in a living cell. Then, we further confirmed their interactions in thecytoplasm using fluorescence resonance energy transfer (FRET) methodology.
To narrow down the binding domain with ANG in progranulin, we constructed aseries of truncated fragments of progranulin into vector pEXP-AD502 and evaluatedtheir interactions with angiogenin in yeast cells. Data showed that either theN-terminal PGF domain or C-terminal DE domain interacted with angiogenin,indicating that binding of angiogenin requires at least two tandem domains. Thefollowing FRET analysis and GST pull-down assay further confirmed the interactionsbetween grnPGF or grnDE with angiogenin. Meanwhile, the binding sites and keyamino acids in angiogenin were explored. The results showed that the smallestfragment binding to progranulin in angiogenin was from amino acid 63 to 110, but nokey amino acids were detected.
We were then curious about the biological consequences of the interaction betweenangiogenin and progranulin. Based on the fact that progranulin inhibits angiogeinnuclear translocation, we speculated that progranulin or its binding domains mayregulate angiogenin's nuclear function. To test that hypothesis, an ABE-luciferasereporter system was applied. The results showed that the expression level of luciferase in HeLa cells transfected with pGL3E-ABE was nearly 30 times higher than thosetransfected with pGL3E vector, indicating ABE acted as a promoter. Whenco-transfected with angiogenin-expressing plasmid, the activity of luciferaseincreased greatly, indicating that ABE's promoter activity was ANG-dependent.Progranulin had no effect on ABE's promotor activity, as the luciferase expressionlevel did not change much in progranulin co-transfection group. When the cells wereco-transfected with both angiogenin and progranulin, the ABE activity reduced to thebasic level, indicating that progranulin inhibited angiogenin's ABE-driven activity.Correspondingly, grnPGF and grnDE both inhibited angiogenin's ABE-drivenactivity. All these evidence suggested that progranulin or its domains may play as anangiogenin regulator.
Therefore, innovative conclusions could be drawn based on the data:
1. Progranulin is one of the angiogenin-interacting proteins.
2. Either grnPGF or grnDE is responsible for angiogenin binding.
3. The smallest fragment interacting with progranulin in angiogenin is from aminoacid 63 to 110.
4. Progranulin, grnPGF or grnDE is a functional regulator of angiogenin.
引文
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