细胞凋亡中Cyclin A-Cdk2底物的筛选及其功能研究
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摘要
细胞凋亡,又称程序性细胞死亡,在维持多细胞生物发育和自稳平衡中发挥着重要作用。细胞凋亡的过盛和缺失皆可导致大量疾病的发生。因此,阐明细胞凋亡中信号转导机制,实现细胞凋亡的有效调控,成为了现代医学、药学界的核心研究目标。
本论文研究发现,Cdk2酶活力在紫杉醇诱导HeLa细胞凋亡的过程中快速上调,而p21CIP1或无活性的点突变Cdk2(Cdk2-dn)的过表达能够有效抑制紫杉醇诱导HeLa细胞的凋亡,线粒体膜电位的去极化,Cytochrome c的释放以及Caspase-3的激活。这些结果表明,Cdk2可以通过调控线粒体膜电位的去极化和Cytochrome c的释放调控细胞凋亡。
为了寻找Cyclin A-Cdk2在细胞凋亡中的特异性底物,我们克隆、表达、纯化了Bcl-2家族蛋白质: Bad,Bid,Bmf,BimS,Bik。通过体外激酶实验,我们发现Cyclin A-Cdk2只对促凋亡蛋白质Bad有磷酸化作用,而另外四种蛋白质则没有被Cyclin A-Cdk2磷酸化。在细胞内,我们也发现了Cyclin A-Cdk2对Bad蛋白质的磷酸化修饰。结合生物信息学分析,通过激酶实验证明了Cyclin A-Cdk2磷酸化Bad蛋白质的91位丝氨酸。在进一步功能研究中发现,Bad蛋白质91位丝氨酸的磷酸化介导了该蛋白质本身的促凋亡功能,表明Cyclin A-Cdk2对细胞凋亡的调控可能是通过对Bad蛋白质的磷酸化实现的。
Apoptosis, or programmed cell death, plays a central role in the development and homeostasis of all multi-cellular organisms. Apoptosis defined exact process by gene regulation, and uncontrolled apoptosis will lead to a large number of difficulty miscellaneous diseases, such as cancers, autoimmune diseases, neurodegenerative diseases etc. Therefore, to investigate the signal transduction mechanism and to achieve effective control of apoptosis become the important research goal in modern Medicine and Pharmacy.
Into the 1990s, apoptosis research has become a hot topic of the biological field. The mechanisms of apoptosis have been more understood at the present time, and there are two main apoptosis pathways summarized: First, through caspase-8 of the uptake of apoptosis surface activate pathway; the other one is the release of Cytochrome c and Samc from mitochondria. Cytochrome c and the cytoplasm Apaf-1, caspase-9 precursor, ATP / dATP formated apoptotic bodies, trigger caspases cascade, lead to cell death. Cell-surface receptor-mediated apoptosis need to be amplified through mitochondrial pathway in some cells where caspase-8 activity can not sufficiently trigger apoptisis. Therefore, mitochondrial is the control center for apoptosis. A series of results showed that the Bcl-2 family members regulating the mitochondrial Cytochrome c release directly or indirectly. However, how the complex cell apoptosis stimuli (such as DNA damage, the loss of growth factors, ROS, etc.) pass to the Bcl-2 family and mitochondria is still not entirely clear.
Cyclin-dependent kinase (Cdks) is a serine / threonine protein kinase, play a central role in cell cycle. In the different cell cycle phases different Cdk is activated. Then phosphorylate their specific substrate to drive the cell cycle. However, recent studies show that a series of specific Cdks (Cdk2, Cdc2, and Cdk4) involved in the regulation of apoptosis. The regulation effect of Cdk2 in apoptosis has been commonly recognized. For example, etoposide-induced apoptosis in human leukemia cells, loss of growth factors caused apoptosis in HUVEC cells, UV irradiation induced apoptosis in mesangial cells, on these processes Cdk2 are specifically activated. And the enzyme activity is apoptosis required. In particular, scientists found that inhibition of Cdk2 activity specifically by small molecule inhibitors can effectively block chemotherapy-induced apoptosis of hair follicle epithelial cells in animal models.
Even other research teams have found that the regulatory role of Cdk2 in apoptosiss. It is not yet been clarified that how activation of Cdk2 related to cell apoptosis pass the signal into the cell on the apoptosis pathway. Using different means (high-level expression of endogenous Cdk2 inhibitory protein p21CIP1, p27KIP1, a non-active point mutation Cdk2 (Cdk2-dn), or the small molecule inhibitors for Cdk2) to inhibit Cdk2 activity, the cells death were prevented. Therefore, we believe that the role of Cdk2 regulation on apoptosis may be achieved through phosphorylating certain substrate proteins; and these substrates are different from those substrates by enzyme-driven in cell cycle. There should be the Cyclin A-Cdk2 specific substrate in apoptosis. Discovery apoptotic Cdk2 substrate would be a key step for studying the mechanism of enzyme regulating apoptosis.
In this paper we draw some conlusions as follows:
1. We provide evidence for the first time, that Cyclin A-Cdk2 activity was upregulated and this event required for the progression of apoptosis of HeLa cells induced by treatment with Paclitaxel;
2. Cyclin A-Cdk2 plays an important role in the mitochondrial membrane potential depolarization and leading to the release of Cytochrome c, we supposed Cyclin A-Cdk2 could affect the mitochondrial pathway to carry out regulation of apoptosis through regulation of mitochondrial membrane permeability;
3. We found a apoptotic Cyclin A-Cdk2 substrate, Bad. And indentified its phosphorylation site, serine 91;
4. The phosphorylation of Bad enhances its pro-apoptotic activity after phosphorylation at serine 91 by Cyclin A-Cdk2.
In this study we demonstrate the essential role of Cdk2 activity in paclitaxel-induced HeLa cell apoptosis process, and provide evidence for the possible signal transduction mechanism of Cdk2 in the apotosis regulation pathway. In addition, we found a new Cyclin A-Cdk2 substrate, Bad, and indentified its phosphorylation site. Through further functional study we propose that in some extent the regulation of cyclin A-Cdk2 in apoptosis process may be mediated by phosphorylting. These results may provide a new target for developing novel cancer reagents.
本论文研究发现,Cdk2酶活力在紫杉醇诱导HeLa细胞凋亡的过程中快速上调,而p21CIP1或无活性的点突变Cdk2(Cdk2-dn)的过表达能够有效抑制紫杉醇诱导HeLa细胞的凋亡,线粒体膜电位的去极化,Cytochrome c的释放以及Caspase-3的激活。这些结果表明,Cdk2可以通过调控线粒体膜电位的去极化和Cytochrome c的释放调控细胞凋亡。
为了寻找Cyclin A-Cdk2在细胞凋亡中的特异性底物,我们克隆、表达、纯化了Bcl-2家族蛋白质: Bad,Bid,Bmf,BimS,Bik。通过体外激酶实验,我们发现Cyclin A-Cdk2只对促凋亡蛋白质Bad有磷酸化作用,而另外四种蛋白质则没有被Cyclin A-Cdk2磷酸化。在细胞内,我们也发现了Cyclin A-Cdk2对Bad蛋白质的磷酸化修饰。结合生物信息学分析,通过激酶实验证明了Cyclin A-Cdk2磷酸化Bad蛋白质的91位丝氨酸。在进一步功能研究中发现,Bad蛋白质91位丝氨酸的磷酸化介导了该蛋白质本身的促凋亡功能,表明Cyclin A-Cdk2对细胞凋亡的调控可能是通过对Bad蛋白质的磷酸化实现的。
Apoptosis, or programmed cell death, plays a central role in the development and homeostasis of all multi-cellular organisms. Apoptosis defined exact process by gene regulation, and uncontrolled apoptosis will lead to a large number of difficulty miscellaneous diseases, such as cancers, autoimmune diseases, neurodegenerative diseases etc. Therefore, to investigate the signal transduction mechanism and to achieve effective control of apoptosis become the important research goal in modern Medicine and Pharmacy.
Into the 1990s, apoptosis research has become a hot topic of the biological field. The mechanisms of apoptosis have been more understood at the present time, and there are two main apoptosis pathways summarized: First, through caspase-8 of the uptake of apoptosis surface activate pathway; the other one is the release of Cytochrome c and Samc from mitochondria. Cytochrome c and the cytoplasm Apaf-1, caspase-9 precursor, ATP / dATP formated apoptotic bodies, trigger caspases cascade, lead to cell death. Cell-surface receptor-mediated apoptosis need to be amplified through mitochondrial pathway in some cells where caspase-8 activity can not sufficiently trigger apoptisis. Therefore, mitochondrial is the control center for apoptosis. A series of results showed that the Bcl-2 family members regulating the mitochondrial Cytochrome c release directly or indirectly. However, how the complex cell apoptosis stimuli (such as DNA damage, the loss of growth factors, ROS, etc.) pass to the Bcl-2 family and mitochondria is still not entirely clear.
Cyclin-dependent kinase (Cdks) is a serine / threonine protein kinase, play a central role in cell cycle. In the different cell cycle phases different Cdk is activated. Then phosphorylate their specific substrate to drive the cell cycle. However, recent studies show that a series of specific Cdks (Cdk2, Cdc2, and Cdk4) involved in the regulation of apoptosis. The regulation effect of Cdk2 in apoptosis has been commonly recognized. For example, etoposide-induced apoptosis in human leukemia cells, loss of growth factors caused apoptosis in HUVEC cells, UV irradiation induced apoptosis in mesangial cells, on these processes Cdk2 are specifically activated. And the enzyme activity is apoptosis required. In particular, scientists found that inhibition of Cdk2 activity specifically by small molecule inhibitors can effectively block chemotherapy-induced apoptosis of hair follicle epithelial cells in animal models.
Even other research teams have found that the regulatory role of Cdk2 in apoptosiss. It is not yet been clarified that how activation of Cdk2 related to cell apoptosis pass the signal into the cell on the apoptosis pathway. Using different means (high-level expression of endogenous Cdk2 inhibitory protein p21CIP1, p27KIP1, a non-active point mutation Cdk2 (Cdk2-dn), or the small molecule inhibitors for Cdk2) to inhibit Cdk2 activity, the cells death were prevented. Therefore, we believe that the role of Cdk2 regulation on apoptosis may be achieved through phosphorylating certain substrate proteins; and these substrates are different from those substrates by enzyme-driven in cell cycle. There should be the Cyclin A-Cdk2 specific substrate in apoptosis. Discovery apoptotic Cdk2 substrate would be a key step for studying the mechanism of enzyme regulating apoptosis.
In this paper we draw some conlusions as follows:
1. We provide evidence for the first time, that Cyclin A-Cdk2 activity was upregulated and this event required for the progression of apoptosis of HeLa cells induced by treatment with Paclitaxel;
2. Cyclin A-Cdk2 plays an important role in the mitochondrial membrane potential depolarization and leading to the release of Cytochrome c, we supposed Cyclin A-Cdk2 could affect the mitochondrial pathway to carry out regulation of apoptosis through regulation of mitochondrial membrane permeability;
3. We found a apoptotic Cyclin A-Cdk2 substrate, Bad. And indentified its phosphorylation site, serine 91;
4. The phosphorylation of Bad enhances its pro-apoptotic activity after phosphorylation at serine 91 by Cyclin A-Cdk2.
In this study we demonstrate the essential role of Cdk2 activity in paclitaxel-induced HeLa cell apoptosis process, and provide evidence for the possible signal transduction mechanism of Cdk2 in the apotosis regulation pathway. In addition, we found a new Cyclin A-Cdk2 substrate, Bad, and indentified its phosphorylation site. Through further functional study we propose that in some extent the regulation of cyclin A-Cdk2 in apoptosis process may be mediated by phosphorylting. These results may provide a new target for developing novel cancer reagents.
引文
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