组蛋白乙酰化修饰对多头绒泡菌细胞周期调控的影响及作用机制的研究
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摘要
真核生物细胞周期沿着G1→S→G2→M的顺序有序地进行。对G1→S，S→G2，G2→M以及走出M期各转换点的调控，保证了细胞周期各事件按次序正常发生，是细胞正常分裂、增殖和生长的保障。真核细胞周期调控的引擎分子是细胞周期素(Cyclin)和细胞周期素依赖性蛋白激酶(cyclin-dependent kinase，CDK)。CDK只有与Cyclin结合在一起才具有激酶活性，CDK是催化亚基，Cyclin是调节亚基。不同的Cyclin和不同CDK的结合、分离、磷酸化和去磷酸化，推动着细胞周期的进程和各检查点的过渡。细胞周期素依赖性蛋白激酶抑制蛋白(cyclin-dependent kinase inhibitor，CDI)是CDK的负调控因子。另外，癌基因和抑癌基因也在细胞周期调控中起到关键作用，癌基因如：myc，ras等；抑癌基因如：P53，P21，P16等等。它们的异常表达可能导致与细胞增殖与分化相关基因转录的异常，从而使细胞周期调节失控。
人们很早就注意到，真核细胞中核小体核心组蛋白N-端尾部的乙酰化水平与基因活化密切相关。随着研究的深入，人们发现组蛋白乙酰化修饰对真核细胞周期调控过程起重要作用，但对其具体的调控机制还了解不多。在真核细胞周期调控的重要检验点G1/S和G2/M，以及其他的转换点S/G2和走出M期的各个过程中，哪些细胞周期调控相关蛋白的表达活性与细胞内的组蛋白乙酰化水平相关?组蛋白乙酰化修饰对这些细胞周期相关蛋白表达水平的调节是通过何种途径来完成的?这些都是我们急于解决的问题。这些问题的解决将有助于我们深入了解组蛋白乙酰化修饰对真核细胞周期调控的作用机制。
本文以多头绒泡菌为实验材料，利用其天然同步化的优点，从新的角度研究了组蛋白乙酰化修饰对真核细胞周期调控的作用机制。初步确定了组蛋白乙酰化在多头绒泡菌细胞周期各转换点的调控过程中对细胞周期调控相关蛋白表达水平的调节作用；了解了组蛋白乙酰化修饰对细胞周期各转换点调控的作用途径；建立了组蛋白乙酰化修饰
对多头绒泡菌细胞周期调控机制的基本模型。得到的上要结果和结沦
如下：
1．通过用组蛋白去乙酚化酶抑制剂 TSA分别处理 S期、＊ 期和dijfl）j
细胞的方法，结合光镜观察和蛋白免疫印迹实验，发现TSA处理抑
制了S期，GZ期和前期多头绒泡菌细胞内组蛋白去乙酚化酶的活
性，使核心组蛋白状的U 的乙酚化水平明显提高，从而打破了
细胞内原有的核心组蛋臼N端尾部的乙酚化修饰水平的平衡。多头
绒泡菌细胞内组蛋白H3 的LSs的超乙酚化，阻断了多头绒泡菌细
胞周期山S／GZ，GZ／M，以及走出M期过程的转换，使之无法）E成
正常的有丝分裂。同时TSA对多头绒泡菌细胞周期的作用具有剂量
依赖性和时间依赖性。山此确定了组蛋白乙酞化修饰对多头绒泡菌
细胞周期S／GZ、GZ川以及走出M期各转换过程的重要作用。
2．通过1”SA处理、RT干CR和蛋白兔疫印迹实验，发现多头绒泡菌细
胞中存在着哺乳动物细胞周期调控相关回于的同源物，包括细胞周
期素类 Cycl in BI蛋白、癌基因产物类 c－Foo和类 c－J。n蛋白、抑
癌基因产物类P53蛋白以及与信号转导相关的类Ras蛋白。这些炎
白的表达水平具有细胞周期依赖性，随着细胞周期的进行而发生变
化。TSA处理引起的多头绒泡菌S期、GZ期和前期细胞内组蛋白
H3乙酚化水平的提高，改变了细胞内类 Cyclin BI蛋白、类。－F。。、
类c－厂n蛋白和类P53蛋白的表达水平，也改变了两种R。。基U
Pnr。sl和 Pnranl的 mRNA以及类hs蛋白的表达水平，从而使细
胞周期无法完成S／GZ、GZ川以及走出M期各转换点的过渡。山此
推测，组蛋白乙酚化修饰对多头绒泡菌细胞周期 S／GZ、（；2川以及
走出M期各转换点的调控可能是通过改变细胞周期调控相关囚－F
的基回mRNA及蛋白的表达水平来完成的。
3．通过抗c－Fos，c－Jun和 Ras蛋白抗体的抗体处理实验，乡合刘细
胞周期进程的观察，发现多头绒泡菌细胞内一定量的具有功能活性
的类c－Fos、类c－Jun蛋白和类他s蛋白在细胞周期UGZ、（ZZ川
以及走出M期的转换过程起重要作用。蛋白免疫印迹分析的结果表
IV
明，当S期、GZ期和前期细胞内具有功能活性的类Ras蛋白的量
减少时，细胞中的细胞周期调控因于类Cyclin BI蛋白、类c－Jun
蛋白、类C－FOS蛋白和类P53蛋白的表达水平，与未经抗体处理时
相比发生了变化（或升高或下降）；而山抗体处理引起的多头绒泡
菌细胞内具有功能活性的类c－Fos和类c－Jun蛋白的减少，使细胞
内类 Cyclin BI蛋白和类 P53蛋白的表达水平与抗体未处理时相比
也发生了明显的改变。这些改变导致细胞无法正常完成S／GZ、GZ川
以及走出M期的转换。由此认为，类c－Fos，类c－Jun和类Ras蛋
白对多头绒泡菌细胞周期各转换点调控可能与细胞周期调控相关
因于蛋?
The precise control of the key checkpoints of the cell cycle, such as G1/S, S/G2, G2/M and mitosis exit, ensures the eukaryotic cells to proliferate and divide in an orderly and programmed manner. The promoting molecules in cell cycle regulation include cyclins and CDKs (cyclin-dependent kinases). The CDKs are activated when they interact and bind with the proper regulating cyclins. It has been shown that different CDKs are responsible for the regulation of cell cycle progression by associating or dissociating the specific cyclins to phosphorylate or dephosphorylate specific substrates. CDIs (cyclin-dependent kinase inhibitors) are the negative effectors to CDKs. Moreover, some oncogenes and tumor suppressor genes are also important in cell cycle regulation; those include myc, ras, p53, p21 and p16. The abnormal expression of these genes may interfere with the normal transcription of certain genes associated with cell cycle progression and cell proliferation.
It has been known for some time that the acetylation of N-termini of core histones in nucleosome is associated with gene activation. Upon extensive studies, it has been found that histone acetylation is important in cell cycle regulation. However, little is known about the mechanisms of this process up to date. We do not know what cell cycle-associated proteins are regulated by histone acetylation modification, especially at the checkpoints of G1/S, S/G2, G2/M and mitosis exit. Neither do we know about the manner in which histone acetylation regulates the expression of these genes. These issues are essential to the understanding of the nature of cell cycle control, and to elucidating the roles of the histone acetylation modification in cell cycle regulation in eukaryotes.
In this thesis, we studied the mechanisms of histone acetylation in cell cycle regulation in Physarum polycephalum, a naturally synchronized slime mold. The results of this study confirmed that histone acetylation changed the expression of proteins related with the regulation of checkpoint conversion in cell cycle. Based on the data arising from the experiments in this thesis, a hypothesized model, which intends to explain
the mechanisms and relationship between histone acetylation and the expression of important cell cycle regulating factors in Physarum polycephalum. The main results and conclusions of this thesis are as follows.
1. By treating the cells in S, G2 phase and prophase with histone deacetylase inhibitor TSA, and through the application of microscopic observation and Western-blotting, we demonstrated that histone acetylation modification played important roles in the cell cycle regulation in Physarum polycephalum, affecting the normal crossover of the checkpoints of S/G2, G2/M and mitosis exit.
2. By using TSA treatment, RT-PCR and Western-blotting, we established that the histone acetylation modification changed the expression of various cell cycle-related factors (mRNA and protein expression) at different checkpoints. These factors included cyclin B1-like protein, P53-like protein, c-Fos-like protein, c-Jun-like protein and Ras-like protein in Physarum polycephalum.
3. To investigate the functions of these factors, cells were treated with anti-c-Fos, anti-c-Jun and anti-Ras antibodies and examined microscopically for the cell cycle progression. The results indicated that c-Fos-like protein, c-Jun-like protein and Ras-like protein played important roles in checkpoint regulation in Physarum polycephalum. Western blot analysis showed that the c-Fos-like protein and c-Jun-like protein may act in cell cycle checkpoint by changing the cyclin B1-like protein and P53-like protein expression; and the Ras-like protein may act by changing the cyclin Bl-like protein , P53-like protein, c-Fos-like protein and c-Jun-like protein expression.
4. Though TSA treatment and Western blotting, we demonstrated that acetylation of certain non-histones may also be associated with the regulation of checkpoints in Physarum polycephalum.
5
人们很早就注意到，真核细胞中核小体核心组蛋白N-端尾部的乙酰化水平与基因活化密切相关。随着研究的深入，人们发现组蛋白乙酰化修饰对真核细胞周期调控过程起重要作用，但对其具体的调控机制还了解不多。在真核细胞周期调控的重要检验点G1/S和G2/M，以及其他的转换点S/G2和走出M期的各个过程中，哪些细胞周期调控相关蛋白的表达活性与细胞内的组蛋白乙酰化水平相关?组蛋白乙酰化修饰对这些细胞周期相关蛋白表达水平的调节是通过何种途径来完成的?这些都是我们急于解决的问题。这些问题的解决将有助于我们深入了解组蛋白乙酰化修饰对真核细胞周期调控的作用机制。
本文以多头绒泡菌为实验材料，利用其天然同步化的优点，从新的角度研究了组蛋白乙酰化修饰对真核细胞周期调控的作用机制。初步确定了组蛋白乙酰化在多头绒泡菌细胞周期各转换点的调控过程中对细胞周期调控相关蛋白表达水平的调节作用；了解了组蛋白乙酰化修饰对细胞周期各转换点调控的作用途径；建立了组蛋白乙酰化修饰
对多头绒泡菌细胞周期调控机制的基本模型。得到的上要结果和结沦
如下：
1．通过用组蛋白去乙酚化酶抑制剂 TSA分别处理 S期、＊ 期和dijfl）j
细胞的方法，结合光镜观察和蛋白免疫印迹实验，发现TSA处理抑
制了S期，GZ期和前期多头绒泡菌细胞内组蛋白去乙酚化酶的活
性，使核心组蛋白状的U 的乙酚化水平明显提高，从而打破了
细胞内原有的核心组蛋臼N端尾部的乙酚化修饰水平的平衡。多头
绒泡菌细胞内组蛋白H3 的LSs的超乙酚化，阻断了多头绒泡菌细
胞周期山S／GZ，GZ／M，以及走出M期过程的转换，使之无法）E成
正常的有丝分裂。同时TSA对多头绒泡菌细胞周期的作用具有剂量
依赖性和时间依赖性。山此确定了组蛋白乙酞化修饰对多头绒泡菌
细胞周期S／GZ、GZ川以及走出M期各转换过程的重要作用。
2．通过1”SA处理、RT干CR和蛋白兔疫印迹实验，发现多头绒泡菌细
胞中存在着哺乳动物细胞周期调控相关回于的同源物，包括细胞周
期素类 Cycl in BI蛋白、癌基因产物类 c－Foo和类 c－J。n蛋白、抑
癌基因产物类P53蛋白以及与信号转导相关的类Ras蛋白。这些炎
白的表达水平具有细胞周期依赖性，随着细胞周期的进行而发生变
化。TSA处理引起的多头绒泡菌S期、GZ期和前期细胞内组蛋白
H3乙酚化水平的提高，改变了细胞内类 Cyclin BI蛋白、类。－F。。、
类c－厂n蛋白和类P53蛋白的表达水平，也改变了两种R。。基U
Pnr。sl和 Pnranl的 mRNA以及类hs蛋白的表达水平，从而使细
胞周期无法完成S／GZ、GZ川以及走出M期各转换点的过渡。山此
推测，组蛋白乙酚化修饰对多头绒泡菌细胞周期 S／GZ、（；2川以及
走出M期各转换点的调控可能是通过改变细胞周期调控相关囚－F
的基回mRNA及蛋白的表达水平来完成的。
3．通过抗c－Fos，c－Jun和 Ras蛋白抗体的抗体处理实验，乡合刘细
胞周期进程的观察，发现多头绒泡菌细胞内一定量的具有功能活性
的类c－Fos、类c－Jun蛋白和类他s蛋白在细胞周期UGZ、（ZZ川
以及走出M期的转换过程起重要作用。蛋白免疫印迹分析的结果表
IV
明，当S期、GZ期和前期细胞内具有功能活性的类Ras蛋白的量
减少时，细胞中的细胞周期调控因于类Cyclin BI蛋白、类c－Jun
蛋白、类C－FOS蛋白和类P53蛋白的表达水平，与未经抗体处理时
相比发生了变化（或升高或下降）；而山抗体处理引起的多头绒泡
菌细胞内具有功能活性的类c－Fos和类c－Jun蛋白的减少，使细胞
内类 Cyclin BI蛋白和类 P53蛋白的表达水平与抗体未处理时相比
也发生了明显的改变。这些改变导致细胞无法正常完成S／GZ、GZ川
以及走出M期的转换。由此认为，类c－Fos，类c－Jun和类Ras蛋
白对多头绒泡菌细胞周期各转换点调控可能与细胞周期调控相关
因于蛋?
The precise control of the key checkpoints of the cell cycle, such as G1/S, S/G2, G2/M and mitosis exit, ensures the eukaryotic cells to proliferate and divide in an orderly and programmed manner. The promoting molecules in cell cycle regulation include cyclins and CDKs (cyclin-dependent kinases). The CDKs are activated when they interact and bind with the proper regulating cyclins. It has been shown that different CDKs are responsible for the regulation of cell cycle progression by associating or dissociating the specific cyclins to phosphorylate or dephosphorylate specific substrates. CDIs (cyclin-dependent kinase inhibitors) are the negative effectors to CDKs. Moreover, some oncogenes and tumor suppressor genes are also important in cell cycle regulation; those include myc, ras, p53, p21 and p16. The abnormal expression of these genes may interfere with the normal transcription of certain genes associated with cell cycle progression and cell proliferation.
It has been known for some time that the acetylation of N-termini of core histones in nucleosome is associated with gene activation. Upon extensive studies, it has been found that histone acetylation is important in cell cycle regulation. However, little is known about the mechanisms of this process up to date. We do not know what cell cycle-associated proteins are regulated by histone acetylation modification, especially at the checkpoints of G1/S, S/G2, G2/M and mitosis exit. Neither do we know about the manner in which histone acetylation regulates the expression of these genes. These issues are essential to the understanding of the nature of cell cycle control, and to elucidating the roles of the histone acetylation modification in cell cycle regulation in eukaryotes.
In this thesis, we studied the mechanisms of histone acetylation in cell cycle regulation in Physarum polycephalum, a naturally synchronized slime mold. The results of this study confirmed that histone acetylation changed the expression of proteins related with the regulation of checkpoint conversion in cell cycle. Based on the data arising from the experiments in this thesis, a hypothesized model, which intends to explain
the mechanisms and relationship between histone acetylation and the expression of important cell cycle regulating factors in Physarum polycephalum. The main results and conclusions of this thesis are as follows.
1. By treating the cells in S, G2 phase and prophase with histone deacetylase inhibitor TSA, and through the application of microscopic observation and Western-blotting, we demonstrated that histone acetylation modification played important roles in the cell cycle regulation in Physarum polycephalum, affecting the normal crossover of the checkpoints of S/G2, G2/M and mitosis exit.
2. By using TSA treatment, RT-PCR and Western-blotting, we established that the histone acetylation modification changed the expression of various cell cycle-related factors (mRNA and protein expression) at different checkpoints. These factors included cyclin B1-like protein, P53-like protein, c-Fos-like protein, c-Jun-like protein and Ras-like protein in Physarum polycephalum.
3. To investigate the functions of these factors, cells were treated with anti-c-Fos, anti-c-Jun and anti-Ras antibodies and examined microscopically for the cell cycle progression. The results indicated that c-Fos-like protein, c-Jun-like protein and Ras-like protein played important roles in checkpoint regulation in Physarum polycephalum. Western blot analysis showed that the c-Fos-like protein and c-Jun-like protein may act in cell cycle checkpoint by changing the cyclin B1-like protein and P53-like protein expression; and the Ras-like protein may act by changing the cyclin Bl-like protein , P53-like protein, c-Fos-like protein and c-Jun-like protein expression.
4. Though TSA treatment and Western blotting, we demonstrated that acetylation of certain non-histones may also be associated with the regulation of checkpoints in Physarum polycephalum.
5
引文
1．汪堃仁等．细胞生物学．北京师范大学出版社．1998，第2版，436-511．
2．沈珝琲，方福德．真核基因表达调控．高等教育出版社·施普林格出版社，1997，修订版．1-14
3．黄百渠，曾庆华等．组蛋白和核小体在基因转录中的作用．科学通报，2000，45(19)：2033—2040．
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