Septin1，一个人类淋巴细胞特异表达基因的功能研究
摘要
septin是人们在筛选芽殖酵母控制细胞周期的温度敏感型突变体时发现的一类与细胞周期调控相关的基因。随着生物学的飞速发展,人们在除植物以外的几乎所有真核生物中发现了这一类基因的存在,并发现其功能绝不仅仅在胞质分裂过程中体现,septin可能参与了细胞极化,细胞骨架重建,胞膜运动,囊跑运输和胞吞胞吐等多个过程,在细胞的生长过程中可能起到着多种重要的功能。但对其在哺乳动物中的功能信息及机制还报道不多。
本文首次鉴定了septin1是一个人类淋系白细胞特异表达的基因,利用RNA干扰技术降低它在T淋巴瘤细胞Jurkat中的表达能够引起细胞G2/M期减少,死亡增加,因此我们认为它对淋巴细胞的生长、增殖起着重要的作用,是细胞进入分裂期所必须的。
其次,我们首次发现septin1能够受到人CK2激酶的磷酸化修饰,同时它还具有与γ-Tubulin相互作用的能力。CK2激酶对septin1 206位ser的磷酸化修饰直接影响了septin1对细胞进入分裂期的调控,从而对细胞的生长,增殖产生影响。由于septin1与γ-Tubulin存在相互作用,提示我们septin1很可能通过与Tubulin骨架发生关系,从而完成其对细胞周期及增殖的调控。
Septin1的组织表达特异性和其功能重要性提示我们,该基因具备了很好的成为特异性免疫抑制剂及淋巴肿瘤治疗药物筛选的药靶的潜力。因此,为了获得其三维结构,便于我们筛选小分子药物,我们利用点突变,获得了可结晶的septin1突变体,并获得了该突变体的晶体,及分辨率达到2.5 A°的衍射数据。为研究该家族的空间结构做出了初步的贡献。
The septins are a novel family of proteins that were first recognized in yeast as proteins associated with the cell cycle control. Septins are broadly expressed throughout the animal kingdom, and yet seem to be absent from plants . Although septins were originally identified as a protein family involved in cytokinesis, recent advances in the field have now ascribed additional functions to these proteins, they are now known to have diverse cellular roles which include polarity determination, cytoskeletal reorganization, membrane dynamics, vesicle trafficking, and exocytosis. They do some important function in cell growth and mitosis.
In this paper, we first identified human septin1 is a lymphocyte specially expressed protein. When septin1 is knock down in human T lymphoma cell line(Jurkat), it will lead to cell death and cell cycle arrest. These results suggest septin1 is necessary for mitosis of lymphocyte, and it will be important for lymphocyte growth and proliferation.
We find septin1 can be phosphorylated by human CK2 kinase in lymphocyte. CK2 kinase can phosphorylate septin1 in 206 serinine resicue. This modify will affect septin1's function in cell cycle control directly. We also find septin1 can be interact with humanγ—Tubulin. This result suggest septin1 perhaps do its function by influencing microtubles' organization or dynamics.
The special expression and important fuction make septin1 own the potential to become a target to screen out the small molecular that can be used for inhibitor of lymphocyte and lymphoma. We try to get the structure of septin1 in order to screen out the small molecular inhibitor. Using the site mutation technic, we get the mutant that can be crystallized. This septin 1 mutant was crystallized and diffraction data were collected to 2.5 A°resolution. This work lay a foundation for the research of septin's structure.
本文首次鉴定了septin1是一个人类淋系白细胞特异表达的基因,利用RNA干扰技术降低它在T淋巴瘤细胞Jurkat中的表达能够引起细胞G2/M期减少,死亡增加,因此我们认为它对淋巴细胞的生长、增殖起着重要的作用,是细胞进入分裂期所必须的。
其次,我们首次发现septin1能够受到人CK2激酶的磷酸化修饰,同时它还具有与γ-Tubulin相互作用的能力。CK2激酶对septin1 206位ser的磷酸化修饰直接影响了septin1对细胞进入分裂期的调控,从而对细胞的生长,增殖产生影响。由于septin1与γ-Tubulin存在相互作用,提示我们septin1很可能通过与Tubulin骨架发生关系,从而完成其对细胞周期及增殖的调控。
Septin1的组织表达特异性和其功能重要性提示我们,该基因具备了很好的成为特异性免疫抑制剂及淋巴肿瘤治疗药物筛选的药靶的潜力。因此,为了获得其三维结构,便于我们筛选小分子药物,我们利用点突变,获得了可结晶的septin1突变体,并获得了该突变体的晶体,及分辨率达到2.5 A°的衍射数据。为研究该家族的空间结构做出了初步的贡献。
The septins are a novel family of proteins that were first recognized in yeast as proteins associated with the cell cycle control. Septins are broadly expressed throughout the animal kingdom, and yet seem to be absent from plants . Although septins were originally identified as a protein family involved in cytokinesis, recent advances in the field have now ascribed additional functions to these proteins, they are now known to have diverse cellular roles which include polarity determination, cytoskeletal reorganization, membrane dynamics, vesicle trafficking, and exocytosis. They do some important function in cell growth and mitosis.
In this paper, we first identified human septin1 is a lymphocyte specially expressed protein. When septin1 is knock down in human T lymphoma cell line(Jurkat), it will lead to cell death and cell cycle arrest. These results suggest septin1 is necessary for mitosis of lymphocyte, and it will be important for lymphocyte growth and proliferation.
We find septin1 can be phosphorylated by human CK2 kinase in lymphocyte. CK2 kinase can phosphorylate septin1 in 206 serinine resicue. This modify will affect septin1's function in cell cycle control directly. We also find septin1 can be interact with humanγ—Tubulin. This result suggest septin1 perhaps do its function by influencing microtubles' organization or dynamics.
The special expression and important fuction make septin1 own the potential to become a target to screen out the small molecular that can be used for inhibitor of lymphocyte and lymphoma. We try to get the structure of septin1 in order to screen out the small molecular inhibitor. Using the site mutation technic, we get the mutant that can be crystallized. This septin 1 mutant was crystallized and diffraction data were collected to 2.5 A°resolution. This work lay a foundation for the research of septin's structure.
引文
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2.Sanders SL,Field CM.Cell division.Septins in common? CurrBiol 1994;4:907-910.
3.Chant J.Septin scaffolds and cleavage planes in Saccharomyces.Cell 1996;84:187-190.
4.Cooper JA,Kiehart DP.Septins may form a ubiquitous familyof cytoskeletal filaments.J Cell Biol 1996;134:1345-1348.
5.Longtine MS,DeMarini D J,Valencik ML,et al.The septins:roles in cytokinesis and other processes.Curr Opin Cell Biol1996;8:106-119.
6.Hartwell LH.Genetic control of the cell division cycle in yeast(Ⅳ).Genes controlling bud emergence and cytokinesis.Exp CellRes 1971;69:265-276.
7.Byers B,Goetsch L.A highly ordered ring of membrane associated filaments in budding yeast.J Cell Biol.1976;69:717-721.
8.DiDomenico B J,Brown NH,Lupieella J,Greene JR,Yanko M,Koltin Y:Homologs of the yeast neck filament sssodated germs:isolation and sequence analysia of Candida albicans CDC3 and CDCIG Mol Gen Genet 1994,242:689-698.
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11.Fares HF,Peifer M,Pringle JR:Localization and possible functions of Drosophila septlns.Mol Biol Cell 1995,6:1843-185g.
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22.Kinoshita M.Assembly of mammalian septins.JBiochem(Tokyo) 2003;134:491-496.
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