p52SHC1和p52SHC3对神经元、神经干细胞和PC12细胞周期的影响研究
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摘要
成年动物的神经元已经退出细胞周期,不再具有分裂增殖的能力。有报道认为同源分子SHC1和SHC3在神经系统中的分布截然相反,前者仅存在于神经干细胞和前体细胞,后者仅存在于分裂后的神经元。此发现为研究神经元脱离细胞周期的分子机理提供契机。因此我们希望通过研究SHC1和SHC3对可分裂细胞(如NSC)和不可分裂细胞(如神经元)细胞周期的影响,解释神经元为何脱离细胞周期。在此目的下,本文主要探讨分别干涉SHC3和SHC1或者分别表达SHC1和SHC3对神经元和神经干细胞周期的影响,研究过表达SHC1和SHC3及其结构域对PC12细胞周期的影响,揭示SHC3的CH1+SH2结构域促进PC12细胞增殖的分子机理。
本文的研究主要分为以下3部分:
第一部分:SHC1和SHC3对神经元和神经干细胞周期的影响研究。在研究SHC1和SHC3对神经元细胞周期的影响时,我们首先从胎鼠中分离并纯化了皮层神经元,进一步的SHC3染色显示神经元的纯度在99%以上,然后用慢病毒介导的RNAi沉默神经元中SHC3 mRNA,用腺病毒在神经元中表达SHC1。SHC3 mRNA干涉后,部分神经元进入细胞周期并伴随着Cyclin D1、Cyclin E、Cyclin A、CDK2和磷酸化CDK2(p-CDK2)表达高调;表达SHC1后,神经元细胞周期没有发生变化,但是Cyclin A、CDK2和p-CDK2的表达出现高调。在研究SHC1和SHC3对神经干细胞(NSC)周期的影响时,我们首先从胎鼠皮层中分离并鉴定了大鼠NSC,然后用慢病毒介导的RNAi沉默神经干细胞中的SHC1,用腺病毒在神经干细胞中表达SHC3。SHC1 mRNA干涉后,神经干细胞周期被抑制伴随着Cyclin E和Cyclin A表达下调;表达SHC3后,神经干细胞发生细胞周期阻滞并伴随着Cyclin D1、Cyclin E和Cyclin A表达下调。
第二部分:SHC1、SHC3及其结构域对PC12细胞周期的影响。我们成功克隆了小鼠p52SHC1和p52SHC3的ORF,构建了SHC1、SHC1-PTB、SHC1-PTB+CH1、SHC1-SH2、SHC1-CH1+SH2、SHC3、SHC3-PTB、SHC3-PTB+CH1、SHC3-SH2、SHC3-CH1+SH2的真核表达载体,利用上述真核表达载体转染PC12细胞,使用流式细胞术和Western Blot分别检测了过表达以上蛋白对PC12细胞周期和细胞周期蛋白的影响。通过流式细胞术的检测,我们发现在转染后36h和60h的PC12细胞中,CH1结构域的存在会影响PTB结构域和SH2结构域的功能,因此在比较PTB和SH2结构域的功能时,必须考虑CH1结构域的存在。流式细胞术和Western Blot检测的结果表明:SHC1提高了CDK2的表达,促使G0/G1期细胞数目减少,SHC3则降低了Cyclin D1和CyclinA的表达,使细胞滞留在G0/G1期;SHC1的PTB结构域能促进Cyclin D1的表达,降低Cyclin A的表达,但是对G0/G1期细胞数目影响不明显,而SHC3的PTB结构域则能降低Cyclin A、Cyclin D1和Cyclin E的表达,使得G0/G1期的细胞比例上升;SHC1和SHC3的SH2结构域均能上调Cyclin D1和Cyclin E的表达,降低G0/G1期细胞的数量,但是SHC3的SH2结构域还能提高CDK2的表达,因此其造成的细胞学效应要比前者大。比较不同结构域引起的细胞学效应,对不同分子来说,SHC3的PTB结构域和SH2结构域要大于SHC1的相应结构域;在同一分子中,对SHC1来说,SH2结构域和PTB结构域的作用差别不明显,对SHC3而言,PTB结构域的功能大于SH2结构域。
第三部分:SHC3的SH2结构域影响PC12细胞周期的分子机理。首先我们使用计算生物学的方法预测了CH1结构域以不同方式结合对其与GRB2结合力的影响,结果发现CH1结构域以正向(从N-末端到C-末端)方式结合的结合能要小于其以反向(从C-末端到N-末端)方式结合的结合能,而GRB2参与的信号通路与细胞增殖正相关,这就导致结合力越大促进细胞增值的能力越强。然后我们使用PCR扩增了SHC3的SH2结构域和CH1结构域,人为将两者的位置颠倒,即由原来的CH1+SH2(反向)变为SH2+CH1(正向),构建了pEGFP-SH2+CH1真核表达载体。最后将pEGFP-CH1+SH2和pEGFP-SH2+CH1转染PC12细胞,使用Co-IP检测CH1+SH2以及SH2+CH1与内源性GRB2的结合力差别,流式细胞术和Western Blot分别检测细胞周期和细胞周期相关蛋白的变化。Co-IP检测显示,CH1+SH2与GRB2的结合力要远大于SH2+CH1的结合力。流式细胞术和Western Blot检测证明CH1+SH2提高了Cyclin D1、Cyclin E和CDK2的表达,促使G0/G1期细胞数目减少,说明CH1+SH2能促进PC12细胞进入细胞周期,而SH2+ CH1则降低了Cyclin A、Cyclin D1和Cyclin E的表达,使G0/G1期细胞数目增加,说明SH2+ CH1抑制了PC12细胞的增殖。
对比研究SHC1和SHC3对神经元和神经干细胞周期的影响,我们发现SHC3在维持神经元的静息状态中起着极其重要的作用,它有可能为众多的中枢神经系统退行性变疾患的治疗提供可能的作用靶点。过表达SHC1、SHC3及其结构域对PC12细胞周期影响的研究初步解释了在脱离细胞周期中SHC3的PTB结构域对它的功能起着主要作用。对SHC3的SH2结构域影响PC12细胞周期分子机理的研究证明SHC3的CH1结构域在向下游传递信号时具有方向性,提示我们CH1结构域以不同方式结合下游分子时会产生不同的细胞学效应
Adult neuron has been out of cell cycle and has no ability to divide and proliferate any more. It was reported that the homolog, SHC1 and SHC3, had totally different distribution in nervous system: the former existed in neural stem/progenitor cells which were found to be largely devoid of SHC3 while the later expressed only in post-mitotic neurons where SHC1 was not found. This phenomenon provides us a base to study the molecular mechanism that neurons are absent from cell cycle. In order to explain the mechanism, effects of p52SHC1 and p52SHC3 on the cell cycle of dividing cells (NSC) and non-dividing cells (neurons) need to be studied. So in this paper, we study the influence of RNAi silencing of SHC3 mRNA and SHC1 mRNA or overexpression of SHC1 and SHC3 on the cell cycles of neurons and NSC, respectively, discuss the effects of overexpressed SHC1, SHC3 and their domains on PC12 cell cycle, investigate the molecular mechanism that the CH1+SH2 domain of SHC3 promotes the proliferation of PC12 cells.
This paper mostly includes the following three parts:
PartⅠ: The effects of SHC1 and SHC3 on the cell cycle of neurons and NSC. To investigate the effects of SHC1 and SHC3 on the cell cycle of neurons, primary neurons were isolated from rat cortex and then enriched to more than 99% purity which testified by SHC3 immuno-staining. Then, lentivirus mediated RNAi was used to silence the mRNA of SHC3 and adenovirus was used to express SHC1 in neurons. After the silencing of SHC3 mRNA, part of neurons re-enter to the cell cycle accompany by upregulation of Cyclin D1, Cyclin E, Cyclin A, CDK2 and phospholated CDK2 (p-CDK2). When SHC1 was expressed, the cell cycle of neurons was not changed, but the levels of Cyclin A, CDK2 and p-CDK2 were elevated. In order to study the effect of SHC1 and SHC3 on the cell cycle of NSC, NSC was isolated from rat cortex and then identified. Then, lentivirus mediated RNAi was used to silencing the mRNA of SHC1 and adenovirus was used to express SHC3 in NSC. After the silencing of SHC1 mRNA, the cell cycle of NSC was blocked and the expression of Cyclin E and Cyclin A was downregulated. When SHC3 was expressed, the cell cycle of NSC was also blocked and expression of Cyclin D1, Cyclin E and Cyclin A was downregulated.
PartⅡ: The effects of overexpressed SHC1, SHC3 and their domains on PC12 cell cycle. In this part, the ORFs of p52SHC1 and p52 SHC3 were successfully cloned from mouse, and then eukaryotic expression vectors of SHC1, SHC3 and their domains (including SHC1, SHC1-PTB, SHC1-PTB+CH1, SHC1-SH2, SHC1-CH1+SH2, SHC3, SHC3-PTB, SHC3-PTB+CH1, SHC3-SH2 and SHC3-CH1+SH2) were constructed. The PC12 cell cycle and expression levels of cell cycle related proteins (Cyclin A, Cyclin D1, Cyclin E and CDK2) were detected by flow cytometry and Western Blot, respectively, after PC12 cells were transfected with these vectors. The fact that existence of CH1 domain affected the functions of PTB domain and SH2 domain of SHC1 and SHC3 was found in the 36h and 60h transfected PC12 cells through flow cytometry analysis. So the CH1 domain was considered when the functions of PTB domain and SH2 domain were investigated. The results of Western Blot and flow cytometry showed that SHC1 promoted the expression of CDK2 and decreased the number of G0/G1 phase cells, while SHC3 lowered the expression of Cylin A and cyclin E and arrested the cell cycle to G0/G1 phase; the PTB domain of SHC1 up regulated the amount of Cyclin D1 and down regulated the amount of Cyclin A, but had little effect on cell cycle of PC12 cells, while PTB domain of SHC3 down regulated the amount of Cyclin A, Cyclin D1 and Cyclin E and increased the number of G0/G1 phase cells; both the SH2 domains of SHC1 and SHC3 enhanced the expression of Cyclin D1 and Cyclin E and caused decrease of G0/G1 phase cells, but SH2 domain of SHC3 also promoted the expression of CDK2, so the decrease of G0/G1 phase cells triggering by over expression of SH2 domain of SHC3 was greater than that of SH2 domain of SHC1. Comparing the functions of different domains in SHC1 and SHC3, it can be infered that to different molecules, the PTB domain and SH2 domain of SHC3 seems more functional to the cell cycle than those of SHC1 and to the same molecule, the functional difference of PTB domain and SH2 domain of SHC1 seems little, but the function of PTB domain of SHC3 is stronger than that of SH2 domain.
PartⅢ: Melecular mechanism that SH2 domain of SHC3 influences the PC12 cell cycle . The binding energy of CH1 domain in different ways with GRB2 was computed and the result showed that the binding energy of normal pattern(from N-terminal to C-terminal) was higher than that of adverse pattern(from C-terminal to N-terminal). Because cell proliferation can be caused by GRB2 related signal pathways, so the higher binding energy, the more proliferated cells. Firstly, we amplified the SH2 domain and CH1 domain of SHC3 by PCR, inverted the location of SH2 domain and CH1 domain by changing CH1+SH2 into SH2+CH1, and constructed the eukaryotic expression vector of SHC3-SH2+CH1. Secondly, CH1+SH2 and SH2+CH1 expression vectors were transfected into PC12 cells. At last, Co-IP was used to detected the binding differences between CH1+SH2 and SH2+CH1 with endogenous GRB2 and flow cyometry and Western Blot were used to detected the changes of cell cycle and expression levels of different cell cycle related proteins after transfected for 36h. The results suggested that CH1+SH2 had higher affinity with GRB2 than that of SH2+CH1 and CH1+SH2 promoted the amounts of cyclin D1, cyclin E and CDK2 and reduced the number of G0/G1 phase cells which indicated that CH1+SH2 enhanced the proliferation of PC12 cells, but SH2+CH1 down regulated the expression of cyclin A, cyclin D1 and cyclin E and increased the number of G0/G1 phase cells which meant the cell proliferation was inhibited.
The study of effects of SHC1 and SHC3 on the cell cycle of neurons and NSC shows that SHC3 plays an important role in mainteining the quiescent condition of neurons and may provide potential target for curing the central nervous system degenerative diseases.It can be concluded the PTB domain of SHC3, plays a main role in the function of SHC3 and CH1 domain of SHC3 has direction in transmitting the cell signals to the downstream signal molecules which infers that different binding ways of CH1 domain to the downstream molecules may cause different cytological effect.
本文的研究主要分为以下3部分:
第一部分:SHC1和SHC3对神经元和神经干细胞周期的影响研究。在研究SHC1和SHC3对神经元细胞周期的影响时,我们首先从胎鼠中分离并纯化了皮层神经元,进一步的SHC3染色显示神经元的纯度在99%以上,然后用慢病毒介导的RNAi沉默神经元中SHC3 mRNA,用腺病毒在神经元中表达SHC1。SHC3 mRNA干涉后,部分神经元进入细胞周期并伴随着Cyclin D1、Cyclin E、Cyclin A、CDK2和磷酸化CDK2(p-CDK2)表达高调;表达SHC1后,神经元细胞周期没有发生变化,但是Cyclin A、CDK2和p-CDK2的表达出现高调。在研究SHC1和SHC3对神经干细胞(NSC)周期的影响时,我们首先从胎鼠皮层中分离并鉴定了大鼠NSC,然后用慢病毒介导的RNAi沉默神经干细胞中的SHC1,用腺病毒在神经干细胞中表达SHC3。SHC1 mRNA干涉后,神经干细胞周期被抑制伴随着Cyclin E和Cyclin A表达下调;表达SHC3后,神经干细胞发生细胞周期阻滞并伴随着Cyclin D1、Cyclin E和Cyclin A表达下调。
第二部分:SHC1、SHC3及其结构域对PC12细胞周期的影响。我们成功克隆了小鼠p52SHC1和p52SHC3的ORF,构建了SHC1、SHC1-PTB、SHC1-PTB+CH1、SHC1-SH2、SHC1-CH1+SH2、SHC3、SHC3-PTB、SHC3-PTB+CH1、SHC3-SH2、SHC3-CH1+SH2的真核表达载体,利用上述真核表达载体转染PC12细胞,使用流式细胞术和Western Blot分别检测了过表达以上蛋白对PC12细胞周期和细胞周期蛋白的影响。通过流式细胞术的检测,我们发现在转染后36h和60h的PC12细胞中,CH1结构域的存在会影响PTB结构域和SH2结构域的功能,因此在比较PTB和SH2结构域的功能时,必须考虑CH1结构域的存在。流式细胞术和Western Blot检测的结果表明:SHC1提高了CDK2的表达,促使G0/G1期细胞数目减少,SHC3则降低了Cyclin D1和CyclinA的表达,使细胞滞留在G0/G1期;SHC1的PTB结构域能促进Cyclin D1的表达,降低Cyclin A的表达,但是对G0/G1期细胞数目影响不明显,而SHC3的PTB结构域则能降低Cyclin A、Cyclin D1和Cyclin E的表达,使得G0/G1期的细胞比例上升;SHC1和SHC3的SH2结构域均能上调Cyclin D1和Cyclin E的表达,降低G0/G1期细胞的数量,但是SHC3的SH2结构域还能提高CDK2的表达,因此其造成的细胞学效应要比前者大。比较不同结构域引起的细胞学效应,对不同分子来说,SHC3的PTB结构域和SH2结构域要大于SHC1的相应结构域;在同一分子中,对SHC1来说,SH2结构域和PTB结构域的作用差别不明显,对SHC3而言,PTB结构域的功能大于SH2结构域。
第三部分:SHC3的SH2结构域影响PC12细胞周期的分子机理。首先我们使用计算生物学的方法预测了CH1结构域以不同方式结合对其与GRB2结合力的影响,结果发现CH1结构域以正向(从N-末端到C-末端)方式结合的结合能要小于其以反向(从C-末端到N-末端)方式结合的结合能,而GRB2参与的信号通路与细胞增殖正相关,这就导致结合力越大促进细胞增值的能力越强。然后我们使用PCR扩增了SHC3的SH2结构域和CH1结构域,人为将两者的位置颠倒,即由原来的CH1+SH2(反向)变为SH2+CH1(正向),构建了pEGFP-SH2+CH1真核表达载体。最后将pEGFP-CH1+SH2和pEGFP-SH2+CH1转染PC12细胞,使用Co-IP检测CH1+SH2以及SH2+CH1与内源性GRB2的结合力差别,流式细胞术和Western Blot分别检测细胞周期和细胞周期相关蛋白的变化。Co-IP检测显示,CH1+SH2与GRB2的结合力要远大于SH2+CH1的结合力。流式细胞术和Western Blot检测证明CH1+SH2提高了Cyclin D1、Cyclin E和CDK2的表达,促使G0/G1期细胞数目减少,说明CH1+SH2能促进PC12细胞进入细胞周期,而SH2+ CH1则降低了Cyclin A、Cyclin D1和Cyclin E的表达,使G0/G1期细胞数目增加,说明SH2+ CH1抑制了PC12细胞的增殖。
对比研究SHC1和SHC3对神经元和神经干细胞周期的影响,我们发现SHC3在维持神经元的静息状态中起着极其重要的作用,它有可能为众多的中枢神经系统退行性变疾患的治疗提供可能的作用靶点。过表达SHC1、SHC3及其结构域对PC12细胞周期影响的研究初步解释了在脱离细胞周期中SHC3的PTB结构域对它的功能起着主要作用。对SHC3的SH2结构域影响PC12细胞周期分子机理的研究证明SHC3的CH1结构域在向下游传递信号时具有方向性,提示我们CH1结构域以不同方式结合下游分子时会产生不同的细胞学效应
Adult neuron has been out of cell cycle and has no ability to divide and proliferate any more. It was reported that the homolog, SHC1 and SHC3, had totally different distribution in nervous system: the former existed in neural stem/progenitor cells which were found to be largely devoid of SHC3 while the later expressed only in post-mitotic neurons where SHC1 was not found. This phenomenon provides us a base to study the molecular mechanism that neurons are absent from cell cycle. In order to explain the mechanism, effects of p52SHC1 and p52SHC3 on the cell cycle of dividing cells (NSC) and non-dividing cells (neurons) need to be studied. So in this paper, we study the influence of RNAi silencing of SHC3 mRNA and SHC1 mRNA or overexpression of SHC1 and SHC3 on the cell cycles of neurons and NSC, respectively, discuss the effects of overexpressed SHC1, SHC3 and their domains on PC12 cell cycle, investigate the molecular mechanism that the CH1+SH2 domain of SHC3 promotes the proliferation of PC12 cells.
This paper mostly includes the following three parts:
PartⅠ: The effects of SHC1 and SHC3 on the cell cycle of neurons and NSC. To investigate the effects of SHC1 and SHC3 on the cell cycle of neurons, primary neurons were isolated from rat cortex and then enriched to more than 99% purity which testified by SHC3 immuno-staining. Then, lentivirus mediated RNAi was used to silence the mRNA of SHC3 and adenovirus was used to express SHC1 in neurons. After the silencing of SHC3 mRNA, part of neurons re-enter to the cell cycle accompany by upregulation of Cyclin D1, Cyclin E, Cyclin A, CDK2 and phospholated CDK2 (p-CDK2). When SHC1 was expressed, the cell cycle of neurons was not changed, but the levels of Cyclin A, CDK2 and p-CDK2 were elevated. In order to study the effect of SHC1 and SHC3 on the cell cycle of NSC, NSC was isolated from rat cortex and then identified. Then, lentivirus mediated RNAi was used to silencing the mRNA of SHC1 and adenovirus was used to express SHC3 in NSC. After the silencing of SHC1 mRNA, the cell cycle of NSC was blocked and the expression of Cyclin E and Cyclin A was downregulated. When SHC3 was expressed, the cell cycle of NSC was also blocked and expression of Cyclin D1, Cyclin E and Cyclin A was downregulated.
PartⅡ: The effects of overexpressed SHC1, SHC3 and their domains on PC12 cell cycle. In this part, the ORFs of p52SHC1 and p52 SHC3 were successfully cloned from mouse, and then eukaryotic expression vectors of SHC1, SHC3 and their domains (including SHC1, SHC1-PTB, SHC1-PTB+CH1, SHC1-SH2, SHC1-CH1+SH2, SHC3, SHC3-PTB, SHC3-PTB+CH1, SHC3-SH2 and SHC3-CH1+SH2) were constructed. The PC12 cell cycle and expression levels of cell cycle related proteins (Cyclin A, Cyclin D1, Cyclin E and CDK2) were detected by flow cytometry and Western Blot, respectively, after PC12 cells were transfected with these vectors. The fact that existence of CH1 domain affected the functions of PTB domain and SH2 domain of SHC1 and SHC3 was found in the 36h and 60h transfected PC12 cells through flow cytometry analysis. So the CH1 domain was considered when the functions of PTB domain and SH2 domain were investigated. The results of Western Blot and flow cytometry showed that SHC1 promoted the expression of CDK2 and decreased the number of G0/G1 phase cells, while SHC3 lowered the expression of Cylin A and cyclin E and arrested the cell cycle to G0/G1 phase; the PTB domain of SHC1 up regulated the amount of Cyclin D1 and down regulated the amount of Cyclin A, but had little effect on cell cycle of PC12 cells, while PTB domain of SHC3 down regulated the amount of Cyclin A, Cyclin D1 and Cyclin E and increased the number of G0/G1 phase cells; both the SH2 domains of SHC1 and SHC3 enhanced the expression of Cyclin D1 and Cyclin E and caused decrease of G0/G1 phase cells, but SH2 domain of SHC3 also promoted the expression of CDK2, so the decrease of G0/G1 phase cells triggering by over expression of SH2 domain of SHC3 was greater than that of SH2 domain of SHC1. Comparing the functions of different domains in SHC1 and SHC3, it can be infered that to different molecules, the PTB domain and SH2 domain of SHC3 seems more functional to the cell cycle than those of SHC1 and to the same molecule, the functional difference of PTB domain and SH2 domain of SHC1 seems little, but the function of PTB domain of SHC3 is stronger than that of SH2 domain.
PartⅢ: Melecular mechanism that SH2 domain of SHC3 influences the PC12 cell cycle . The binding energy of CH1 domain in different ways with GRB2 was computed and the result showed that the binding energy of normal pattern(from N-terminal to C-terminal) was higher than that of adverse pattern(from C-terminal to N-terminal). Because cell proliferation can be caused by GRB2 related signal pathways, so the higher binding energy, the more proliferated cells. Firstly, we amplified the SH2 domain and CH1 domain of SHC3 by PCR, inverted the location of SH2 domain and CH1 domain by changing CH1+SH2 into SH2+CH1, and constructed the eukaryotic expression vector of SHC3-SH2+CH1. Secondly, CH1+SH2 and SH2+CH1 expression vectors were transfected into PC12 cells. At last, Co-IP was used to detected the binding differences between CH1+SH2 and SH2+CH1 with endogenous GRB2 and flow cyometry and Western Blot were used to detected the changes of cell cycle and expression levels of different cell cycle related proteins after transfected for 36h. The results suggested that CH1+SH2 had higher affinity with GRB2 than that of SH2+CH1 and CH1+SH2 promoted the amounts of cyclin D1, cyclin E and CDK2 and reduced the number of G0/G1 phase cells which indicated that CH1+SH2 enhanced the proliferation of PC12 cells, but SH2+CH1 down regulated the expression of cyclin A, cyclin D1 and cyclin E and increased the number of G0/G1 phase cells which meant the cell proliferation was inhibited.
The study of effects of SHC1 and SHC3 on the cell cycle of neurons and NSC shows that SHC3 plays an important role in mainteining the quiescent condition of neurons and may provide potential target for curing the central nervous system degenerative diseases.It can be concluded the PTB domain of SHC3, plays a main role in the function of SHC3 and CH1 domain of SHC3 has direction in transmitting the cell signals to the downstream signal molecules which infers that different binding ways of CH1 domain to the downstream molecules may cause different cytological effect.
引文
[1] Eric R. Kandel,james H. Schwartz T M J. principals of neural Science. McGraw-Hill Medical, 2000.
[2] Conti L, Sipione S, Magrassi L, et al. Shc signaling in differentiating neural progenitor cells.[J]. Nat Neurosci. 2001, 4(6): 579-586.
[3] Ravichandran K S. Signaling via Shc family adapter proteins.[J]. Oncogene. 2001, 20(44): 6322-6330.
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[6] Pelicci G, Dente L, De Giuseppe A, et al. A family of Shc related proteins with conserved PTB, CH1 and SH2 regions.[J]. Oncogene. 1996, 13(3): 633-641.
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[8] Nakamura T, Muraoka S, Sanokawa R, et al. N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling.[J]. J Biol Chem. 1998, 273(12): 6960-6967.
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[11] Tanabe K, Kiryu-Seo S, Nakamura T, et al. Alternative expression of Shc family members in nerve-injured motoneurons.[J]. Brain Res Mol Brain Res. 1998, 53(1-2): 291-296.
[12] Conti L, De Fraja C, Gulisano M, et al. Expression and activation of SH2/PTB-containing ShcA adaptor protein reflects the pattern of neurogenesis in the mammalian brain.[J]. Proc Natl Acad Sci U S A. 1997, 94(15): 8185-8190.
[13] O'Bryan J P, Songyang Z, Cantley L, et al. A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain.[J]. Proc Natl Acad Sci U S A. 1996, 93(7): 2729-2734.
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[15] Gelderloos J A, Rosenkranz S, Bazenet C, et al. A role for Src in signal relay by the platelet-derived growth factor alpha receptor.[J]. J Biol Chem. 1998, 273(10): 5908-5915.
[16] Schmandt R, Liu S K, Mcglade C J. Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells.[J]. Oncogene. 1999, 18(10): 1867-1879.
[17] Sakai R, Henderson J T, O'Bryan J P, et al. The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons.[J]. Neuron. 2000, 28(3): 819-833.
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[21] Liu H Y, Meakin S O. ShcB and ShcC activation by the Trk family of receptor tyrosine kinases.[J]. J Biol Chem. 2002, 277(29): 26046-26056.
[22] Dhulipala V C, Welshons W V, Reddy C S. Cell cycle proteins in normal and chemically induced abnormal secondary palate development: a review.[J]. Hum Exp Toxicol. 2006, 25(11): 675-682.
[23] Sherr C J. Cell cycle control and cancer.[J]. Harvey Lect. 2000, 96: 73-92.
[24] Aggarwal B B, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives.[J]. Cell Cycle. 2005, 4(9): 1201-1215.
[25] George R, Schuller A C, Harris R, et al. A phosphorylation-dependent gating mechanism controls the SH2 domain interactions of the Shc adaptor protein.[J]. J Mol Biol. 2008, 377(3): 740-747.
[26] Kimura I, Konishi M, Miyake A, et al. Neudesin, a secreted factor, promotes neural cell proliferation and neuronal differentiation in mouse neural precursor cells.[J]. J Neurosci Res. 2006, 83(8): 1415-1424.
[27] Kimura I, Yoshioka M, Konishi M, et al. Neudesin, a novel secreted protein with a unique primary structure and neurotrophic activity.[J]. J Neurosci Res. 2005, 79(3): 287-294.
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[6] Kimura I, Nakayama Y, Yamauchi H, et al. Neurotrophic activity of neudesin, a novel extracellular heme-binding protein, is dependent on the binding of heme to its cytochrome b5-like heme/steroid-binding domain.[J]. J Biol Chem. 2008, 283(7): 4323-4331.
[1] Ravichandran K S, Lee K K, Songyang Z, et al. Interaction of Shc with the zeta chain of the T cell receptor upon T cell activation.[J]. Science. 1993, 262(5135): 902-905.
[2] Marengere L E, Waterhouse P, Duncan G S, et al. Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4.[J]. Science. 1996, 272(5265): 1170-1173.
[3] Iwashima M, Takamatsu M, Yamagishi H, et al. Genetic evidence for Shc requirement in TCR-induced c-Rel nuclear translocation and IL-2 expression.[J]. Proc Natl Acad Sci U S A. 2002, 99(7): 4544-4549.
[4] Zhou M M, Meadows R P, Logan T M, et al. Solution structure of the Shc SH2 domain complexed with a tyrosine-phosphorylated peptide from the T-cell receptor.[J]. Proc Natl Acad Sci U S A. 1995, 92(17): 7784-7788.
[2] Conti L, Sipione S, Magrassi L, et al. Shc signaling in differentiating neural progenitor cells.[J]. Nat Neurosci. 2001, 4(6): 579-586.
[3] Ravichandran K S. Signaling via Shc family adapter proteins.[J]. Oncogene. 2001, 20(44): 6322-6330.
[4] Nakamura T, Muraoka S, Sanokawa R, et al. N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling.[J]. J Biol Chem. 1998, 273(12): 6960-6967.
[5] Kojima T, Yoshikawa Y, Takada S, et al. Genomic organization of the Shc-related phosphotyrosine adapters and characterization of the full-length Sck/ShcB: specific association of p68-Sck/ShcB with pp135.[J]. Biochem Biophys Res Commun. 2001, 284(4): 1039-1047.
[6] Pelicci G, Dente L, De Giuseppe A, et al. A family of Shc related proteins with conserved PTB, CH1 and SH2 regions.[J]. Oncogene. 1996, 13(3): 633-641.
[7] Xie Y, Hung M C. p66Shc isoform down-regulated and not required for HER-2/neu signaling pathway in human breast cancer cell lines with HER-2/neu overexpression.[J]. Biochem Biophys Res Commun. 1996, 221(1): 140-145.
[8] Nakamura T, Muraoka S, Sanokawa R, et al. N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling.[J]. J Biol Chem. 1998, 273(12): 6960-6967.
[9] Nakamura T, Sanokawa R, Sasaki Y, et al. N-Shc: a neural-specific adapter molecule that mediates signaling from neurotrophin/Trk to Ras/MAPK pathway.[J]. Oncogene. 1996, 13(6): 1111-1121.
[10] Pelicci G, Lanfrancone L, Grignani F, et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.[J]. Cell. 1992, 70(1): 93-104.
[11] Tanabe K, Kiryu-Seo S, Nakamura T, et al. Alternative expression of Shc family members in nerve-injured motoneurons.[J]. Brain Res Mol Brain Res. 1998, 53(1-2): 291-296.
[12] Conti L, De Fraja C, Gulisano M, et al. Expression and activation of SH2/PTB-containing ShcA adaptor protein reflects the pattern of neurogenesis in the mammalian brain.[J]. Proc Natl Acad Sci U S A. 1997, 94(15): 8185-8190.
[13] O'Bryan J P, Songyang Z, Cantley L, et al. A mammalian adaptor protein with conserved Src homology 2 and phosphotyrosine-binding domains is related to Shc and is specifically expressed in the brain.[J]. Proc Natl Acad Sci U S A. 1996, 93(7): 2729-2734.
[14] Ravichandran K S, Lee K K, Songyang Z, et al. Interaction of Shc with the zeta chain of the T cell receptor upon T cell activation.[J]. Science. 1993, 262(5135): 902-905.
[15] Gelderloos J A, Rosenkranz S, Bazenet C, et al. A role for Src in signal relay by the platelet-derived growth factor alpha receptor.[J]. J Biol Chem. 1998, 273(10): 5908-5915.
[16] Schmandt R, Liu S K, Mcglade C J. Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells.[J]. Oncogene. 1999, 18(10): 1867-1879.
[17] Sakai R, Henderson J T, O'Bryan J P, et al. The mammalian ShcB and ShcC phosphotyrosine docking proteins function in the maturation of sensory and sympathetic neurons.[J]. Neuron. 2000, 28(3): 819-833.
[18] Luzi L, Confalonieri S, Di Fiore P P, et al. Evolution of Shc functions from nematode to human.[J]. Curr Opin Genet Dev. 2000, 10(6): 668-674.
[19] De Falco V, Guarino V, Malorni L, et al. RAI(ShcC/N-Shc)-dependent recruitment of GAB 1 to RET oncoproteins potentiates PI 3-K signalling in thyroid tumors.[J]. Oncogene. 2005, 24(41): 6303-6313.
[20] Nakazawa T, Nakano I, Sato M, et al. Comparative expression profiles of Trk receptors and Shc-related phosphotyrosine adapters during retinal development: potential roles of N-Shc/ShcC in brain-derived neurotrophic factor signal transduction and modulation.[J]. J Neurosci Res. 2002, 68(6): 668-680.
[21] Liu H Y, Meakin S O. ShcB and ShcC activation by the Trk family of receptor tyrosine kinases.[J]. J Biol Chem. 2002, 277(29): 26046-26056.
[22] Dhulipala V C, Welshons W V, Reddy C S. Cell cycle proteins in normal and chemically induced abnormal secondary palate development: a review.[J]. Hum Exp Toxicol. 2006, 25(11): 675-682.
[23] Sherr C J. Cell cycle control and cancer.[J]. Harvey Lect. 2000, 96: 73-92.
[24] Aggarwal B B, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives.[J]. Cell Cycle. 2005, 4(9): 1201-1215.
[25] George R, Schuller A C, Harris R, et al. A phosphorylation-dependent gating mechanism controls the SH2 domain interactions of the Shc adaptor protein.[J]. J Mol Biol. 2008, 377(3): 740-747.
[26] Kimura I, Konishi M, Miyake A, et al. Neudesin, a secreted factor, promotes neural cell proliferation and neuronal differentiation in mouse neural precursor cells.[J]. J Neurosci Res. 2006, 83(8): 1415-1424.
[27] Kimura I, Yoshioka M, Konishi M, et al. Neudesin, a novel secreted protein with a unique primary structure and neurotrophic activity.[J]. J Neurosci Res. 2005, 79(3): 287-294.
[1] Conti L, Sipione S, Magrassi L, et al. Shc signaling in differentiating neural progenitor cells.[J]. Nat Neurosci. 2001, 4(6): 579-586.
[2] Ke Y, Ho K, Du J, et al. Role of soluble ceruloplasmin in iron uptake by midbrain and hippocampus neurons.[J]. J Cell Biochem. 2006, 98(4): 912-919.
[3] Wagner H P. Cell cycle control and cancer.[J]. Indian J Pediatr. 1998, 65(6): 805-814.
[4] Kasten M M, Giordano A. pRb and the cdks in apoptosis and the cell cycle.[J]. Cell Death Differ. 1998, 5(2): 132-140.
[5] Dhulipala V C, Welshons W V, Reddy C S. Cell cycle proteins in normal and chemically induced abnormal secondary palate development: a review.[J]. Hum Exp Toxicol. 2006, 25(11): 675-682.
[6] Fernandez P L, Jares P, Rey M J, et al. Cell cycle regulators and their abnormalities in breast cancer.[J]. Mol Pathol. 1998, 51(6): 305-309.
[7] Sherr C J. Cell cycle control and cancer.[J]. Harvey Lect. 2000, 96: 73-92.
[8] Mercer W E. Checking on the cell cycle.[J]. J Cell Biochem Suppl. 1998, 30-31: 50-54.
[9] Aggarwal B B, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives.[J]. Cell Cycle. 2005, 4(9): 1201-1215.
[10] Jones N, Hardy W R, Friese M B, et al. Analysis of a Shc family adaptor protein, ShcD/Shc4, that associates with muscle-specific kinase.[J]. Mol Cell Biol. 2007, 27(13): 4759-4773.
[11] Liu H Y, Meakin S O. ShcB and ShcC activation by the Trk family of receptor tyrosine kinases.[J]. J Biol Chem. 2002, 277(29): 26046-26056.
[12] Pelicci G, Troglio F, Bodini A, et al. The neuron-specific Rai (ShcC) adaptor protein inhibits apoptosis by coupling Ret to the phosphatidylinositol 3-kinase/Akt signaling pathway.[J]. Mol Cell Biol. 2002, 22(20): 7351-7363.
[13] Atwal J K, Massie B, Miller F D, et al. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-kinase.[J]. Neuron. 2000, 27(2): 265-277.
[14] Nakamura T, Sanokawa R, Sasaki Y, et al. N-Shc: a neural-specific adapter molecule that mediates signaling from neurotrophin/Trk to Ras/MAPK pathway.[J]. Oncogene. 1996, 13(6): 1111-1121.
[15] Pelicci G, Lanfrancone L, Grignani F, et al. A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction.[J]. Cell. 1992, 70(1): 93-104.
[16] Rozakis-Adcock M, Mcglade J, Mbamalu G, et al. Association of the Shc andGrb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases.[J]. Nature. 1992, 360(6405): 689-692.
[17] Kisielow M, Kleiner S, Nagasawa M, et al. Isoform-specific knockdown and expression of adaptor protein ShcA using small interfering RNA.[J]. Biochem J. 2002, 363(Pt 1): 1-5.
[18] Mcfarland K N, Wilkes S R, Koss S E, et al. Neural-specific inactivation of ShcA results in increased embryonic neural progenitor apoptosis and microencephaly.[J]. J Neurosci. 2006, 26(30): 7885-7897.
[19] Heinrich J N, Kwak S P, Howland D S, et al. Disruption of ShcA signaling halts cell proliferation--characterization of ShcC residues that influence signaling pathways using yeast.[J]. Cell Signal. 2006, 18(6): 795-806.
[20] Lanfrancone L, Pelicci G, Brizzi M F, et al. Overexpression of Shc proteins potentiates the proliferative response to the granulocyte-macrophage colony-stimulating factor and recruitment of Grb2/SoS and Grb2/p140 complexes to the beta receptor subunit.[J]. Oncogene. 1995, 10(5): 907-917.
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