spindlin1诱导细胞中期阻滞及丝裂灾变的研究
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摘要
spin/ssty家族是一个高度保守的生殖细胞成熟发育中高表达的转录子基因家族,被认为在减数分裂和早期胚胎发育的细胞周期调控中扮演重要角色。但对此基因家族功能的研究报道仍然匮乏。在之前的研究中,我们从卵巢癌细胞中克隆鉴定了该家族的人类基因spindlin1,并报道spindlin1亚细胞定位为细胞核内弥散分布,其异常表达能够增加G2/M期细胞比例,恶性转化NIH3T3细胞,使其在移植裸鼠体内后形成肿瘤;我们还获得了spindlin1蛋白的晶体结构,它是由三个串联重复的Tudor样结构域构成,每个结构域均为4～5个反向平行的β折叠所组成的β折叠桶样结构,具有结合超螺旋双链DNA的能力。本实验目的在于进一步探讨spindlin1影响细胞周期,促进肿瘤形成的作用机制。实验结果显示,部分spindlin1蛋白在有丝分裂过程中呈动态分布。在有丝分裂前期、中期主要定位在纺锤体;进入后期,与纺锤体共定位的spindlin1蛋白明显增加,主要在纺锤体中央区富集;当胞质分裂完成后,该蛋白离开微管,特异地集中于子代细胞核定位。与此同时,我们的结果还显示spindlin1蛋白过表达能够引起细胞分裂异常,细胞分裂中期阻滞,丝裂灾变以及基因组不稳定。进一步的分析表明这些表型的出现可能源于spindlin1蛋白与热休克蛋白HSP70、驱动蛋白Kid相互作用,上调Mad2蛋白表达水平,激活纺锤体检测点,干扰有丝分裂中期向后期转换。综上所述,我们认为spindlin1可能参与纺锤体组织,协调染色体在赤道板的排列和姐妹染色体的分离,其异常表达能够影响基因组稳定性,促进细胞的恶性转化。
Spin/ssty gene family is high conserved and very abundant transcript involved in gametogenesis, which was known to play a critical role in cell cycle regulation during meiosis and early embryogenesis. Previously, we have identified human gene spindlin1 as a homologue of spin/ssty gene family from ovarian cancer cells and reported that ectopic expression of spindlin1 could increase the G2/M population,transform NIH3T3 cells and at last induce tumorigenesis in nude mouse. Moreover, we reported the crystal structure of human spindlin1, as consisted of three tandem repeats of Tudor-like domains and showed that spindlin1 possessed dsDNA binding activity and exhibited higher affinity for super helical dsDNA than for open cycle dsDNA. Nevertheless, our knowledge about the members of spin/ssty family in meiosis/mitosis is still fragmentary and the biological roles of spindlin1 in cell cycle and oncogenesis are still largely unknown. Here, our result showed that spindlin1, as a nuclear protein, is relocated during mitosis. Fractions of spindlin1 proteins were localized to the mitotic spindle from prometaphase to metaphase, and were enriched at midzone following anaphase entering. We also showed that ectopic expression of spindlin1 provoked aberrant mitosis, metaphase arrest, mitotic catastrophe, and genomic instability. Furthermore, we found that Mad2 up-regulation, interaction with Hsp70/Kid and activation of spindle checkpoint may contribute to these changes in spindlin1-overexpressed cells. Taken together, these data suggestted that spindin1 may be involved in concordance of chromosome movement, congression and segregation and ectopic expression of spindlin1 was detrimental for genetic stability and can potentially contribute to cancer development.
Spin/ssty gene family is high conserved and very abundant transcript involved in gametogenesis, which was known to play a critical role in cell cycle regulation during meiosis and early embryogenesis. Previously, we have identified human gene spindlin1 as a homologue of spin/ssty gene family from ovarian cancer cells and reported that ectopic expression of spindlin1 could increase the G2/M population,transform NIH3T3 cells and at last induce tumorigenesis in nude mouse. Moreover, we reported the crystal structure of human spindlin1, as consisted of three tandem repeats of Tudor-like domains and showed that spindlin1 possessed dsDNA binding activity and exhibited higher affinity for super helical dsDNA than for open cycle dsDNA. Nevertheless, our knowledge about the members of spin/ssty family in meiosis/mitosis is still fragmentary and the biological roles of spindlin1 in cell cycle and oncogenesis are still largely unknown. Here, our result showed that spindlin1, as a nuclear protein, is relocated during mitosis. Fractions of spindlin1 proteins were localized to the mitotic spindle from prometaphase to metaphase, and were enriched at midzone following anaphase entering. We also showed that ectopic expression of spindlin1 provoked aberrant mitosis, metaphase arrest, mitotic catastrophe, and genomic instability. Furthermore, we found that Mad2 up-regulation, interaction with Hsp70/Kid and activation of spindle checkpoint may contribute to these changes in spindlin1-overexpressed cells. Taken together, these data suggestted that spindin1 may be involved in concordance of chromosome movement, congression and segregation and ectopic expression of spindlin1 was detrimental for genetic stability and can potentially contribute to cancer development.
引文
1 Howlett SK, Bolton VN. Sequence and regulation of morphological and molecular events during the first cell cycle of mouse embryogenesis. J Embryol Exp Morphol, 1985,87:175-206.
2 Levinson J, Goodfellow P, vadeboncoeur M, et al. Identification of stage-specific polypeptides synthesized during murine preimplantation development. Proc Natl Acad Sci U S A, 1978,75:3332-6.
3 Van Blerkom J. Structural relationship and posttranslational modification of stage-specific proteins synthesized during early preimplantation development in the mouse. Proc Natl Acad Sci U S A, 1981,78:7629-33.
4 Cullen BR, Emigholz K,Monahan JJ. Protein patterns of early mouse embryos during development. Differentiation, 1980,17:151-60.
5 Howlett SK. A set of proteins showing cell cycle dependent modification in the early mouse embryo. Cell, 1986,45:387-96.
6 Vitale AM, Calvert ME, Mallavarapu M, et al. Proteomic profiling of murine oocyte maturation. Mol Reprod Dev, 2007,74:608-16.
7 Stitzel ML, Seydoux G. Regulation of the oocyte-to-zygote transition. Science, 2007,316:407-8.
8 Oh B, Hwang SY, Solter D, et al. Spindlin, a major maternal transcript expressed in the mouse during the transition from oocyte to embryo. Development, 1997,124:493-503.
9 Oh B, Hampl A, Eppig JJ, et al. SPIN, a substrate in the MAP kinase pathway in mouse oocytes. Mol Reprod Dev, 1998,50:240-9.
10 Choi T, Fukasawa K, Zhou R, et al. The Mos/mitogen-activated protein kinase (MAPK) pathway regulates the size and degradation of the first polar body in maturing mouse oocytes. Proc Natl Acad Sci U S A, 1996,93:7032-5.
11 Toure A, Szot M, Mahadevaiah SK, et al. A new deletion of the mouse Y chromosome long arm associated with the loss of Ssty expression, abnormal sperm development and sterility. Genetics, 2004,166:901-12.
12 Toure A, Clemente EJ, Ellis P, et al. Identification of novel Y chromosome encoded transcripts by testis transcriptome analysis of mice with deletions of the Y chromosome long arm. Genome Biol, 2005,6:R102.
13 Toure A, Grigoriev V, Mahadevaiah SK, et al. A protein encoded by a member of the multicopy Ssty gene family located on the long arm of the mouse Y chromosome is expressed during sperm development. Genomics, 2004,83:140-7.
14 Staub E, Mennerich D,Rosenthal A. The Spin/Ssty repeat: a new motif identified in proteins involved in vertebrate development from gamete to embryo. Genome Biol, 2002,3:RESEARCH0003.
15 de Kloet RS, de Kloet SR. Evolution of the spindlin gene in birds: independent cessation of the recombination of sex chromosomes at the spindlin locus in neognathous birds and tinamous, a palaeognathous avian family. Genetica, 2003,119:333-42.
16 Itoh Y, Hori T, Saitoh H, et al. Chicken spindlin genes on W and Z chromosomes: transcriptional expression of both genes and dynamic behavior of spindlin in interphase and mitotic cells. Chromosome Res, 2001,9:283-99.
17 Wang XL, Sun M, Mei J, et al. Identification of a Spindlin homolog in gibel carp (Carassius auratus gibelio). Comp Biochem Physiol B Biochem Mol Biol, 2005,141:159-67.
18 Fletcher BS, Dragstedt C, Notterpek L, et al. Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression. Leukemia, 2002,16:1507-18.
19 Yue W, Sun LY, Li CH, et al. [Screening and identification of ovarian carcinomas related genes]. Ai Zheng, 2004,23:141-5.
20 Gao Y, Yue W, Zhang P, et al. Spindlin1, a novel nuclear protein with a role in the transformation of NIH3T3 cells. Biochem Biophys Res Commun, 2005,335:343-50.
21 Zhao Q, Qin L, Jiang F, et al. Structure of human spindlin1. Tandem tudor-like domains for cell cycle regulation. J Biol Chem, 2007,282:647-56.
1 Gao Y, Yue W, Zhang P, et al. Spindlin1, a novel nuclear protein with a role in the transformation of NIH3T3 cells. Biochem Biophys Res Commun, 2005,335:343-50.
2 Itoh Y, Hori T, Saitoh H, et al. Chicken spindlin genes on W and Z chromosomes: transcriptional expression of both genes and dynamic behavior of spindlin in interphase and mitotic cells. Chromosome Res, 2001,9:283-99.
3 Oh B, Hwang SY, Solter D, et al. Spindlin, a major maternal transcript expressed in the mouse during the transition from oocyte to embryo. Development, 1997,124:493-503.
4 Oh B, Hampl A, Eppig JJ, et al. SPIN, a substrate in the MAP kinase pathway in mouse oocytes. Mol Reprod Dev, 1998,50:240-9.
5 Staub E, Mennerich D,Rosenthal A. The Spin/Ssty repeat: a new motif identified in proteins involved in vertebrate development from gamete to embryo. Genome Biol, 2002,3:RESEARCH0003.
6 Wang XL, Sun M, Mei J, et al. Identification of a Spindlin homolog in gibel carp (Carassius auratus gibelio). Comp Biochem Physiol B Biochem Mol Biol, 2005,141:159-67.
7 Zhao Q, Qin L, Jiang F, et al. Structure of human spindlin1. Tandem tudor-like domains for cell cycle regulation. J Biol Chem, 2007,282:647-56.
8 Lancelot N, Charier G, Couprie J, et al. The checkpoint Saccharomyces cerevisiae Rad9 protein contains a tandem tudor domain that recognizes DNA. Nucleic Acids Res, 2007,35:5898-912.
9 Huyen Y, Zgheib O, Ditullio RA Jr, et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature, 2004,432:406-11.
10 Kotani T, Sutomo R, Sasongko TH, et al. A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins. J Neurol, 2007,254:624-30.
11 Fletcher BS, Dragstedt C, Notterpek L, et al. Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression. Leukemia, 2002,16:1507-18.
12 Oh B, Hwang S, McLaughlin J, et al. Timely translation during the mouse oocyte-to-embryo transition. Development, 2000,127:3795-803.
13 Otegui MS, Verbrugghe KJ,Skop AR. Midbodies and phragmoplasts: analogous structures involved in cytokinesis. Trends Cell Biol, 2005,15:404-13.
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1 Wang XL, Sun M, Mei J, et al. Identification of a Spindlin homolog in gibel carp (Carassius auratus gibelio). Comp Biochem Physiol B Biochem Mol Biol, 2005,141:159-67.
2 Itoh Y, Hori T, Saitoh H, et al. Chicken spindlin genes on W and Z chromosomes: transcriptional expression of both genes and dynamic behavior of spindlin in interphase and mitotic cells. Chromosome Res, 2001,9:283-99.
3 Oh B, Hampl A, Eppig JJ, et al. SPIN, a substrate in the MAP kinase pathway in mouse oocytes. Mol Reprod Dev, 1998,50:240-9.
4 Oh B, Hwang SY, Solter D, et al. Spindlin, a major maternal transcript expressed in the mouse during the transition from oocyte to embryo. Development, 1997,124:493-503.
5 Fletcher BS, Dragstedt C, Notterpek L, et al. Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression. Leukemia, 2002,16:1507-18.
6 Gao Y, Yue W, Zhang P, et al. Spindlin1, a novel nuclear protein with a role in the transformation of NIH3T3 cells. Biochem Biophys Res Commun, 2005,335:343-50.
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20 Lancelot N, Charier G, Couprie J, et al. The checkpoint Saccharomyces cerevisiae Rad9 protein contains a tandem tudor domain that recognizes DNA. Nucleic Acids Res, 2007,35:5898-912.
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1 Wang XL, Sun M, Mei J, et al. Identification of a Spindlin homolog in gibel carp (Carassius auratus gibelio). Comp Biochem Physiol B Biochem Mol Biol, 2005,141:159-67.
2 Itoh Y, Hori T, Saitoh H, et al. Chicken spindlin genes on W and Z chromosomes: transcriptional expression of both genes and dynamic behavior of spindlin in interphase and mitotic cells. Chromosome Res, 2001,9:283-99.
3 Oh B, Hampl A, Eppig JJ, et al. SPIN, a substrate in the MAP kinase pathway in mouse oocytes. Mol Reprod Dev, 1998,50:240-9.
4 Oh B, Hwang SY, Solter D, et al. Spindlin, a major maternal transcript expressed in the mouse during the transition from oocyte to embryo. Development, 1997,124:493-503.
5 Lew DJ, Burke DJ. The spindle assembly and spindle position checkpoints. Annu Rev Genet, 2003,37:251-82.
6 Malmanche N, Maia A,Sunkel CE. The spindle assembly checkpoint: preventing chromosome mis-segregation during mitosis and meiosis. FEBS Lett, 2006,580:2888-95.
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20 Blagosklonny MV. Mitotic arrest and cell fate: why and how mitotic inhibition of transcription drives mutually exclusive events. Cell Cycle, 2007,6:70-4.
21 Vink M, Simonetta M, Transidico P, et al. In vitro FRAP identifies the minimal requirements for Mad2 kinetochore dynamics. Curr Biol, 2006,16:755-66.
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24 Winnefeld M, Grewenig A, Schnolzer M, et al. Human SGT interacts with Bag-6/Bat-3/Scythe and cells with reduced levels of either protein display persistence of few misaligned chromosomes and mitotic arrest. Exp Cell Res, 2006,312:2500-14.
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26 Glowala M, Mazurek A, Piddubnyak V, et al. HSP70 overexpression increases resistance of V79 cells to cytotoxicity of airborne pollutants, but does not protect the mitotic spindle against damage caused by airborne toxins. Toxicology, 2002,170:211-9.
27 Tokai-Nishizumi N, Ohsugi M, Suzuki E, et al. The chromokinesin Kid is required for maintenance of propermetaphase spindle size. Mol Biol Cell, 2005,16:5455-63.
28 Brouhard GJ, Hunt AJ. Microtubule movements on the arms of mitotic chromosomes: polar ejection forces quantified in vitro. Proc Natl Acad Sci U S A, 2005,102:13903-8.
29 Levesque AA, Howard L, Gordon MB, et al. A functional relationship between NuMA and kid is involved in both spindle organization and chromosome alignment in vertebrate cells. Mol Biol Cell, 2003,14:3541-52.
30 Ohsugi M, Tokai-Nishizumi N, Shiroguchi K, et al. Cdc2-mediated phosphorylation of Kid controls its distribution to spindle and chromosomes. EMBO J, 2003,22:2091-103.
31 Levesque AA, Compton DA. The chromokinesin Kid is necessary for chromosome arm orientation and oscillation, but not congression, on mitotic spindles. J Cell Biol, 2001,154:1135-46.
32 Tokai N, Fujimoto-Nishiyama A, Toyoshima Y, et al. Kid, a novel kinesin-like DNA binding protein, is localized to chromosomes and the mitotic spindle. EMBO J, 1996,15:457-67.
2 Levinson J, Goodfellow P, vadeboncoeur M, et al. Identification of stage-specific polypeptides synthesized during murine preimplantation development. Proc Natl Acad Sci U S A, 1978,75:3332-6.
3 Van Blerkom J. Structural relationship and posttranslational modification of stage-specific proteins synthesized during early preimplantation development in the mouse. Proc Natl Acad Sci U S A, 1981,78:7629-33.
4 Cullen BR, Emigholz K,Monahan JJ. Protein patterns of early mouse embryos during development. Differentiation, 1980,17:151-60.
5 Howlett SK. A set of proteins showing cell cycle dependent modification in the early mouse embryo. Cell, 1986,45:387-96.
6 Vitale AM, Calvert ME, Mallavarapu M, et al. Proteomic profiling of murine oocyte maturation. Mol Reprod Dev, 2007,74:608-16.
7 Stitzel ML, Seydoux G. Regulation of the oocyte-to-zygote transition. Science, 2007,316:407-8.
8 Oh B, Hwang SY, Solter D, et al. Spindlin, a major maternal transcript expressed in the mouse during the transition from oocyte to embryo. Development, 1997,124:493-503.
9 Oh B, Hampl A, Eppig JJ, et al. SPIN, a substrate in the MAP kinase pathway in mouse oocytes. Mol Reprod Dev, 1998,50:240-9.
10 Choi T, Fukasawa K, Zhou R, et al. The Mos/mitogen-activated protein kinase (MAPK) pathway regulates the size and degradation of the first polar body in maturing mouse oocytes. Proc Natl Acad Sci U S A, 1996,93:7032-5.
11 Toure A, Szot M, Mahadevaiah SK, et al. A new deletion of the mouse Y chromosome long arm associated with the loss of Ssty expression, abnormal sperm development and sterility. Genetics, 2004,166:901-12.
12 Toure A, Clemente EJ, Ellis P, et al. Identification of novel Y chromosome encoded transcripts by testis transcriptome analysis of mice with deletions of the Y chromosome long arm. Genome Biol, 2005,6:R102.
13 Toure A, Grigoriev V, Mahadevaiah SK, et al. A protein encoded by a member of the multicopy Ssty gene family located on the long arm of the mouse Y chromosome is expressed during sperm development. Genomics, 2004,83:140-7.
14 Staub E, Mennerich D,Rosenthal A. The Spin/Ssty repeat: a new motif identified in proteins involved in vertebrate development from gamete to embryo. Genome Biol, 2002,3:RESEARCH0003.
15 de Kloet RS, de Kloet SR. Evolution of the spindlin gene in birds: independent cessation of the recombination of sex chromosomes at the spindlin locus in neognathous birds and tinamous, a palaeognathous avian family. Genetica, 2003,119:333-42.
16 Itoh Y, Hori T, Saitoh H, et al. Chicken spindlin genes on W and Z chromosomes: transcriptional expression of both genes and dynamic behavior of spindlin in interphase and mitotic cells. Chromosome Res, 2001,9:283-99.
17 Wang XL, Sun M, Mei J, et al. Identification of a Spindlin homolog in gibel carp (Carassius auratus gibelio). Comp Biochem Physiol B Biochem Mol Biol, 2005,141:159-67.
18 Fletcher BS, Dragstedt C, Notterpek L, et al. Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression. Leukemia, 2002,16:1507-18.
19 Yue W, Sun LY, Li CH, et al. [Screening and identification of ovarian carcinomas related genes]. Ai Zheng, 2004,23:141-5.
20 Gao Y, Yue W, Zhang P, et al. Spindlin1, a novel nuclear protein with a role in the transformation of NIH3T3 cells. Biochem Biophys Res Commun, 2005,335:343-50.
21 Zhao Q, Qin L, Jiang F, et al. Structure of human spindlin1. Tandem tudor-like domains for cell cycle regulation. J Biol Chem, 2007,282:647-56.
1 Gao Y, Yue W, Zhang P, et al. Spindlin1, a novel nuclear protein with a role in the transformation of NIH3T3 cells. Biochem Biophys Res Commun, 2005,335:343-50.
2 Itoh Y, Hori T, Saitoh H, et al. Chicken spindlin genes on W and Z chromosomes: transcriptional expression of both genes and dynamic behavior of spindlin in interphase and mitotic cells. Chromosome Res, 2001,9:283-99.
3 Oh B, Hwang SY, Solter D, et al. Spindlin, a major maternal transcript expressed in the mouse during the transition from oocyte to embryo. Development, 1997,124:493-503.
4 Oh B, Hampl A, Eppig JJ, et al. SPIN, a substrate in the MAP kinase pathway in mouse oocytes. Mol Reprod Dev, 1998,50:240-9.
5 Staub E, Mennerich D,Rosenthal A. The Spin/Ssty repeat: a new motif identified in proteins involved in vertebrate development from gamete to embryo. Genome Biol, 2002,3:RESEARCH0003.
6 Wang XL, Sun M, Mei J, et al. Identification of a Spindlin homolog in gibel carp (Carassius auratus gibelio). Comp Biochem Physiol B Biochem Mol Biol, 2005,141:159-67.
7 Zhao Q, Qin L, Jiang F, et al. Structure of human spindlin1. Tandem tudor-like domains for cell cycle regulation. J Biol Chem, 2007,282:647-56.
8 Lancelot N, Charier G, Couprie J, et al. The checkpoint Saccharomyces cerevisiae Rad9 protein contains a tandem tudor domain that recognizes DNA. Nucleic Acids Res, 2007,35:5898-912.
9 Huyen Y, Zgheib O, Ditullio RA Jr, et al. Methylated lysine 79 of histone H3 targets 53BP1 to DNA double-strand breaks. Nature, 2004,432:406-11.
10 Kotani T, Sutomo R, Sasongko TH, et al. A novel mutation at the N-terminal of SMN Tudor domain inhibits its interaction with target proteins. J Neurol, 2007,254:624-30.
11 Fletcher BS, Dragstedt C, Notterpek L, et al. Functional cloning of SPIN-2, a nuclear anti-apoptotic protein with roles in cell cycle progression. Leukemia, 2002,16:1507-18.
12 Oh B, Hwang S, McLaughlin J, et al. Timely translation during the mouse oocyte-to-embryo transition. Development, 2000,127:3795-803.
13 Otegui MS, Verbrugghe KJ,Skop AR. Midbodies and phragmoplasts: analogous structures involved in cytokinesis. Trends Cell Biol, 2005,15:404-13.
14 McCollum D. Cytokinesis: the central spindle takes center stage. Curr Biol, 2004,14:R953-5.
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