14-3-3蛋白在人脑星形细胞瘤中的定位研究及意义
|
摘要
星形细胞瘤是指以星形胶质细胞来源的瘤细胞所组成的肿瘤,约占神经上皮源性肿瘤的75%。按肿瘤的生物学特性星形细胞瘤可分两大类:一类边界清楚,较少向周围脑组织浸润,包括毛细胞星形细胞瘤、室管膜下巨细胞性星形细胞瘤与多形性黄色星形细胞瘤,其临床表现与病情发展均有各自的典型特征,预后较好;另一类星形细胞瘤则无明显边界,向周围脑组织广泛浸润,肿瘤细胞呈间变特性,包括星形细胞瘤、间变性星形细胞瘤及多形性胶质母细胞瘤等。此类肿瘤病程为进展性,该肿瘤患者中的大部分即使手术后接受放疗、化疗等综合治疗,疗效依然欠佳。其中,恶性程度最高的多形性胶质母细胞瘤患者经综合治疗后,其中位生存期也仅为1年。在肿瘤的发生、发展中有多种基因的连锁改变,这些改变最终使肿瘤细胞获得无限增殖的生长优势,从而促进肿瘤的发生和发展。肿瘤细胞获得对抗细胞凋亡的能力是其中的关键环节。因此,发现和阐明瘤细胞逃避细胞凋亡的机制有助于研究肿瘤治疗的新方法。
14-3-3蛋白是一类高度保守的小分子多功能酸性二聚体蛋白。它们是在1967年一项有关脑蛋白的研究中被发现的,并根据其在随后的蛋白电泳中的位置而命名的。最初只发现这类蛋白在神经元中有大量的表达,但随后的研究发现它们存在于所有的真核生物中。目前,已发现这类蛋白在哺乳类有机体中有由不同基因编码的7个亚型及200多个能与其相互结合的配体分子。研究还发现14-3-3蛋白在多种细胞生理过程中起重要作用。近年的研究还提示,14-3-3蛋白有可能通过抑制细胞凋亡而参与肿瘤的发生和发展。曹卫东博士曾经研究并证实了14-3-3蛋白在胶质瘤中有表达,但是具体哪一个亚型有表达还需要进一步的研究。基于此,本科题从以下方面进行探讨。
14-3-3蛋白各亚型在人脑星形细胞瘤中的表达及意义:采用免疫组化ABC法检测了10例正常脑组织、80例人脑星形细胞瘤石蜡标本中14-3-3蛋白各亚型的表达情况。结果显示,在正常脑组织中,14-3-3蛋白7个亚型主要表达于神经元胞体和突起,但是ε、ζ和θ亚型在胶质细胞的胞浆中有弱表达。在大部分星形细胞瘤组织中,β、ε、ζ、η和θ亚型都有表达,且它们的免疫反应评分随着肿瘤的级别增高而升高。结果提示,这5个亚型在人脑星形细胞瘤的发生中可能起着重要的作用,尤其是β和η亚型。
综上所述,本课题在国内外首次研究了14-3-3蛋白各亚型在人脑星形细胞瘤中的表达情况,结果表明,β和η亚型可能是人脑星形细胞瘤形成和发展过程中的两个关键亚型,其作用机制可能是它们通过抑制肿瘤细胞凋亡来促进星形细胞瘤的发生和发展,而ε、ζ和θ亚型或许对正常脑的功能有关,并且参与肿瘤的恶性进展,但作用相对较弱。以14-3-3β和η亚型为靶点来设计新的脑星形细胞瘤治疗方法是很有前景的。
Astrocyte tumors are the most frequent brain tumors and are among the most aggressive of all human malignancies. It accounts for about 50%~60% of human brain tumor in adults. Even with best conventional therapy, the prognosis is dismal. The mean survival time after surgical intervention is within one year in glioblastoma multiformes which is the most malignany in astrocytoma. Astrocyte tumors development occurs by means of a series of dynamic changes in the genome that confer growth advantages to transformed cells. Among them, suppression of apoptosis is a common phenomenon. By extending the lifespan of abnormal cells, accumulation of transforming mutations can occur, thereby promoting development of the malignant phenotype and resistance to conventional cytotixic agents. Therefore, futher understanding the mechanism of how astrocytoma cells evading apoptosis is crucial for designing new ways restoration of apoptotic pathways in astrocytomas.
The term14-3-3 refers to family fo highly conserved, small, acidic dimeric proteins of 28-33 kDa. They received their name in 1967 during a systematic classification of brain proteins that was based on their fraction number on anion-exchange chromatography and migration position in gel electrophoresis. Proteins of this family have been found in all eukaryotic organisms studied so far. However, the highest tissue concertration of 14-3-3 proteins is found in the brain,comprising about 1% of its total soluble protein. There are seven known mammalian 14-3-3 proteins encoded by separate genes. Up to now, over 200 14-3-3-binding ligands are identified, and the number of 14-3-3 binding partners is still increasing. Considering the number of binding partners, it is not surprising that 14-3-3 proteins play crucial roles in regulating multiple cellular processes-they include the maintenance of cell cycle checkpoints and DNA repair, the prevention of aoptosis, the onset of cell differentiation and senescence, and the coordination of cell adhesion and motility. In addition to their important roles in many mormal physiology processes, 14-3-3 proteins have attracted much recent interest in the etiopathogenesis of human cancers owing to their involvement in the prevention of apoptosis. At present, there is no research concerning the expression and role of 14-3-3 isoforms in astrocytoma. In this study, we addressed this issue from the following aspect.
The expression and its significance of 14-3-3 isoforms in astrocyte tumors: The expression of 14-3-3 isoforms was detected in 80 cases of formalin-fixed, paraffin embedded archival tumor tissue from patients with astrocyte tumors, and 10 normal human brain tissues by immunohistochemical ABC method. The results showed that, in the normal control brains, 14-3-3 isoforms immunoreactivity was localized mainly in the neuronal somata and processes, while only weak expression ofε,ζandθwas found in some glial cells. Howeverβ,ε,ζ,ηandθisoforms’immunoreactivity was seen in the majority of astrocyte tumor samples and its immunoreactivity score was increased markedly with an increase in the pathologic grade of human astrocyte tumors. These results indicate that the five isoforms ,especiallyβandηisoforms,may play an important role in tumorigenesis of human astrocyte tumors.
In summary, in the first time, this research suggested thatβandηisoforms may be key proteins in initiation and progress of human astrocyte tumors, its mechanism may involve the anti-apoptotic effect of 14-3-3 isoforms in the tumorogenesis and development of astrocyte tumors. 14-3-3 isoforms may be considered as a potential and promising target for gene therapy of astrocyte tumors.
14-3-3蛋白是一类高度保守的小分子多功能酸性二聚体蛋白。它们是在1967年一项有关脑蛋白的研究中被发现的,并根据其在随后的蛋白电泳中的位置而命名的。最初只发现这类蛋白在神经元中有大量的表达,但随后的研究发现它们存在于所有的真核生物中。目前,已发现这类蛋白在哺乳类有机体中有由不同基因编码的7个亚型及200多个能与其相互结合的配体分子。研究还发现14-3-3蛋白在多种细胞生理过程中起重要作用。近年的研究还提示,14-3-3蛋白有可能通过抑制细胞凋亡而参与肿瘤的发生和发展。曹卫东博士曾经研究并证实了14-3-3蛋白在胶质瘤中有表达,但是具体哪一个亚型有表达还需要进一步的研究。基于此,本科题从以下方面进行探讨。
14-3-3蛋白各亚型在人脑星形细胞瘤中的表达及意义:采用免疫组化ABC法检测了10例正常脑组织、80例人脑星形细胞瘤石蜡标本中14-3-3蛋白各亚型的表达情况。结果显示,在正常脑组织中,14-3-3蛋白7个亚型主要表达于神经元胞体和突起,但是ε、ζ和θ亚型在胶质细胞的胞浆中有弱表达。在大部分星形细胞瘤组织中,β、ε、ζ、η和θ亚型都有表达,且它们的免疫反应评分随着肿瘤的级别增高而升高。结果提示,这5个亚型在人脑星形细胞瘤的发生中可能起着重要的作用,尤其是β和η亚型。
综上所述,本课题在国内外首次研究了14-3-3蛋白各亚型在人脑星形细胞瘤中的表达情况,结果表明,β和η亚型可能是人脑星形细胞瘤形成和发展过程中的两个关键亚型,其作用机制可能是它们通过抑制肿瘤细胞凋亡来促进星形细胞瘤的发生和发展,而ε、ζ和θ亚型或许对正常脑的功能有关,并且参与肿瘤的恶性进展,但作用相对较弱。以14-3-3β和η亚型为靶点来设计新的脑星形细胞瘤治疗方法是很有前景的。
Astrocyte tumors are the most frequent brain tumors and are among the most aggressive of all human malignancies. It accounts for about 50%~60% of human brain tumor in adults. Even with best conventional therapy, the prognosis is dismal. The mean survival time after surgical intervention is within one year in glioblastoma multiformes which is the most malignany in astrocytoma. Astrocyte tumors development occurs by means of a series of dynamic changes in the genome that confer growth advantages to transformed cells. Among them, suppression of apoptosis is a common phenomenon. By extending the lifespan of abnormal cells, accumulation of transforming mutations can occur, thereby promoting development of the malignant phenotype and resistance to conventional cytotixic agents. Therefore, futher understanding the mechanism of how astrocytoma cells evading apoptosis is crucial for designing new ways restoration of apoptotic pathways in astrocytomas.
The term14-3-3 refers to family fo highly conserved, small, acidic dimeric proteins of 28-33 kDa. They received their name in 1967 during a systematic classification of brain proteins that was based on their fraction number on anion-exchange chromatography and migration position in gel electrophoresis. Proteins of this family have been found in all eukaryotic organisms studied so far. However, the highest tissue concertration of 14-3-3 proteins is found in the brain,comprising about 1% of its total soluble protein. There are seven known mammalian 14-3-3 proteins encoded by separate genes. Up to now, over 200 14-3-3-binding ligands are identified, and the number of 14-3-3 binding partners is still increasing. Considering the number of binding partners, it is not surprising that 14-3-3 proteins play crucial roles in regulating multiple cellular processes-they include the maintenance of cell cycle checkpoints and DNA repair, the prevention of aoptosis, the onset of cell differentiation and senescence, and the coordination of cell adhesion and motility. In addition to their important roles in many mormal physiology processes, 14-3-3 proteins have attracted much recent interest in the etiopathogenesis of human cancers owing to their involvement in the prevention of apoptosis. At present, there is no research concerning the expression and role of 14-3-3 isoforms in astrocytoma. In this study, we addressed this issue from the following aspect.
The expression and its significance of 14-3-3 isoforms in astrocyte tumors: The expression of 14-3-3 isoforms was detected in 80 cases of formalin-fixed, paraffin embedded archival tumor tissue from patients with astrocyte tumors, and 10 normal human brain tissues by immunohistochemical ABC method. The results showed that, in the normal control brains, 14-3-3 isoforms immunoreactivity was localized mainly in the neuronal somata and processes, while only weak expression ofε,ζandθwas found in some glial cells. Howeverβ,ε,ζ,ηandθisoforms’immunoreactivity was seen in the majority of astrocyte tumor samples and its immunoreactivity score was increased markedly with an increase in the pathologic grade of human astrocyte tumors. These results indicate that the five isoforms ,especiallyβandηisoforms,may play an important role in tumorigenesis of human astrocyte tumors.
In summary, in the first time, this research suggested thatβandηisoforms may be key proteins in initiation and progress of human astrocyte tumors, its mechanism may involve the anti-apoptotic effect of 14-3-3 isoforms in the tumorogenesis and development of astrocyte tumors. 14-3-3 isoforms may be considered as a potential and promising target for gene therapy of astrocyte tumors.
引文
1. Aitken A, Collinge DB, van Heusden BP, et al. 14-3-3 proteins: a highly conserved, widespread family of eukaryotic proteins. Trends Biochem. Sci. 1992,17:498–501.
2. van Heusden GP. 14-3-3 proteins: regulators of numerous eukaryotic proteins. IUBMB Life. 2005, 57(9):623-9.
3. Darling DL, Yingling J, Wynshaw-Boris A. Role of 14-3-3 proteins in eukaryotic signaling and development. Curr Top Dev Biol. 2005, 68:281-315.
4. Bridges D, Moorhead GB. 14-3-3 proteins: a number of functions for a numbered protein. Sci STKE. 2005, 2005(296):re10.
5. Mhawech P. 14-3-3 proteins--an update. Cell Res. 2005, 15(4):228-36.
6. Muslin AJ, Lau JM. Differential functions of 14-3-3 isoforms in vertebrate development. Curr Top Dev Biol. 2005, 65:211-28.
7. Wilker E, Yaffe MB. 14-3-3 Proteins--a focus on cancer and human disease. J Mol Cell Cardiol. 2004, 37(3):633-42.
8. Mackintosh C. Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes. Biochem J. 2004, 381(Pt 2):329-42.
9. Dougherty MK, Morrison DK. Unlocking the code of 14-3-3. J Cell Sci. 2004, 117(Pt 10):1875-84.
10. Hermeking H. The 14-3-3 cancer connection. Nat Rev Cancer. 2003, 3(12):931-43.
11. Siles-Lucas Mdel M, Gottstein B. The 14-3-3 protein: a key molecule in parasites as in other organisms. Trends Parasitol. 2003 Dec;19(12):575-81.
12. Sehnke PC, DeLille JM, Ferl RJ. Consummating signal transduction: the role of 14-3-3 proteins in the completion of signal-induced transitions in protein activity. Plant Cell. 2002,14 Suppl:S339-54.
13. Reuther GW, Pendergast AM. The roles of 14-3-3 proteins in signal transduction. Vitam Horm. 1996, 149-75.
14. Xing H, Zhang S, Weinheimer C, Kovacs A, Muslin AJ. 14-3-3 proteinsblock apoptosis and differentially regulate MAPK cascades. EMBO J. 2000;19: 349–358.
15. Takahashi Y. The 14-3-3 proteins: gene, gene expression, and function. Neurochem Res. 2003, 28(8):1265-73.
16. Fu H, Subramanian RR, Masters SC. 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol. 2000,40:617-47.
17. Aitken A. Functional specificity in 14-3-3 isoform interactions through dimer formation and phosphorylation. Chromosome location of mammalian isoforms and variants. Plant Mol Biol. 2002,50(6):993-1010.
18. Roberts MR. 14-3-3 proteins find new partners in plant cell signalling. Trends Plant Sci. 2003, 8(5):218-23.
19. van Hemert MJ, van Heusden GP, Steensma HY. Yeast 14-3-3 proteins. Yeast. 2001,18(10):889-95.
20. Berg D, Holzmann C, Riess O. 14-3-3 proteins in the nervous system. Nat Rev Neurosci. 2003, 4(9):752-62.
21. Skoulakis EM, Davis RL. 14-3-3 proteins in neuronal development and function. Mol Neurobiol. 1998, 16(3):269-84.
22. Boston PF, Jackson P, Kynoch PAM, Thompson RJ. Purification, properties, and immunohistochemical localisation of human brain 14-3-3 protein. J Neurochem. 1982;38:1466–1474
23. Baxter HC, Liu WG, Forster JL, Aitken A, Fraser JR. Immunolocalisation of 14-3-3 isoforms in normal and scrapie-infected murine brain. Neuroscience. 2002,109(1):5-14.
24. Eckardt NA. Transcription factors dial 14-3-3 for nuclear shuttle. Plant Cell. 2001,13(11):2385-9.
25. Muslin AJ, Xing H. 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell Signal. 2000,12(11-12):703-9.
26. Wang H, Zhang L, Liddington R, Fu H. Mutations in the hydrophobic surface of an amphipathic groove of 14-3-3 zeta disrupt its interaction with Raf-1 kinase [J]. J Biol Chem, 1998, 273(26): 16297-16304.
27. Liu D, Bienkowska J, Petosa C ,et al. Crystal structure of the zeta isoform of the 14-3-3 protein [J]. Nature, 1995, 376(6536): 191-194.
28. Petosa C, Masters SC, Bankston LA, et al. 14-3-3 zeta binds a phosphorylated Raf peptide and an unphosphorylated peptide via its conserved amphipathic groove [J]. J Biol Chem., 1998, 273(26): 16305-16310.
29. Konishi Y,Lehtinen M,Donovan N,et al. CDC2 phosphorylation of BAD links the cell cycle to the cell death machinery [J].Mol Cell,2002,9(5):1005-1016.
30. Nomura M,Shimizu S,Sugiyama T,et al.14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax[J].J Biol Chem,2003,278(3):2058-2065.
31. Brunet A, Bonni A, Zigmond MJ, et a1.Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor [J].Cell,1999,96(6):857-868.
32. Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria [J]. Cell, 1996, 87(4): 629-638.
33. Wilker E, Yaffe MB.14-3-3 proteins-a focus on cancer and human disease [J]. J Mol Cell Cardiol,2004,37(3): 633-642.
34. Dougherty MK, Morrison DK. Unlocking the code of 14-3-3[J].J Cell Sci,2004, 117(Pt10): 1875-1884.
35. Hermeking H. The 14-3-3 cancer connection [J].Nat Rev Cancer,2003, 3(12): 931-43.
36. Suzuki H, Itoh F, Toyota M, et a1. Inactivation of the 14-3-3 sigma gene is associated with 5' CpG island hypermethylation in human cancers [J]. Cancer Res, 2000, 60(16): 4353-4357.
37. Hermeking H, Lengauer C, Polyak K, et al. 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression [J]. Mol Cell, 1997, 1(1):3-11.
38. Chan TA, Hermeking H, Lengauer C, et al.14-3-3σ is required to prevent mitotic catastrophe after DNA damage [J]. Nature, 1999, 401(6753): 616-620.
39. Nacht M, Ferguson AT, Zhang W, et al. Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer [J]. Cancer Res, 1999, 59(21): 5464-5470.
40. Ferguson AT, Evron E, Umbricht CB, et al. High frequency of hypermethylation at the 14-3-3σ locus leads to gene silencing in breast cancer [J]. Proc Natl Acad Sci USA, 2000, 97(11): 6049-6054.
41. Lodygin D, Hermeking H. The role of epigenetic inactivation of
14-3-3sigma in human cancer [J]. Cell Research, 2005, 15(4): 237-246.
42. Qi W, Liu X, Qiao D, Martinez JD. Isoform-specific expression of 14-3-3 proteins in human lung cancer tissues [J].Int J Cancer, 2005, 113(3): 359-363.
43. Takihara Y, Matsuda Y, Hara J. Role of the β-isoform of 14-3-3 proteins in cellular proliferation and oncogenic transformation [J]. Carcinogenesis,2000,21(11): 2073-2077.
44. Sugiyama A, Miyaqi Y, Komiya Y, et al. Forced expression of antisense
14-3-3β RNA suppresses tumor cell growth in vitro and in vivo [J]. Carcinogenesis, 2003,24(9): 1549-1559.
45. Martin D, Brown-Luedi M, Chiquet-Ehrismann R. Tenascin-C signaling through induction of 14-3-3tau [J]. J Cell Biol,2003,160(2):171-175.
46. Villaret DB, Wang T, Dillon D, et al. Identification of genes overexpressed in head and neck squamous cell carcinoma using a combination of complementary DNA subtraction and microarray analysis [J]. Laryngoscope,2000,110(3 Pt 1):374-381.
47. Masters SC, Fu H.14-3-3 proteins mediate an essential anti-apoptotic signal [J].J Biol Chem,2001,276(48):45193-45200.
48. Graves PR, Yu L, Schwarz JK, et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01 [J]. J Biol Chem, 2000,275(8):5600-5605.
49. 章翔, 主编. 神经系统肿瘤学. 北京: 军事医学科学出版社, 1999, 1-35.
50. Sanson M, Thillet J, Hoang-Xuan K. Molecular changes in gliomas. Curr Opin Oncol, 2004, 16(6): 607-613.
51. 张冠中, 肖龙海, 李新钢. 胶质瘤凋亡研究进展. 河北医学. 2004, 10(2): 184-186.
52. Boston PF, Jackson P, Kynoch PAM, Thompson RJ. Purification, properties, and immunohistochemical localisation of human brain 14-3-3 protein. JNeurochem. 1982,38:1466–1474
53. Boston PF, Jackson P, Thompson RJ. Human 14-3-3 protein: radioimmunoassay, tissue distribution, and cerebrospinal fluid levels in patients with neurological disorders. J Neurochem. 1982,38:1475–1482.
54. Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H, Budka H. 14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains. J Neuropathol Exp Neurol. 2002,61:245–253.
55. Kawamoto Y, Akiguchi I, Nakamura S, Budka H. Accumulation of 14-3-3 proteins in glial cytoplasmic inclusions in multiple system atrophy. Ann Neurol. 2002,52:722–731.
56. Kawamoto Y, Akiguchi I, Kovacs GG, Flicker H, Budka H. Increased 14-3-3 immunoreactivity in glial elements in patients with multiple sclerosis. Acta Neuropathol (Berl). 2004,107:137-143.
57. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature, 2001, 411(6835): 342-348.
58. Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer, 2004, 4(8): 592-603.
59. Cheung HH, Arora V, Korneluk RG. Abnormalities of cell structures in tumors: apoptosis in tumors.EXS. 2006, 96:201-21.
60. Staunton MJ, Gaffney EF. Apoptosis: basic concepts and potential significance in human cancer.Arch Pathol Lab Med. 1998 ,122(4):310-9.
61. Rudin CM, Thompson CB: Apoptosis and disease: regulation and clinical relevance of programmed cell death. Annu Rev Med. 1997;48:267–281.
62. Rosenquist M. 14-3-3 proteins in apoptosis. Braz J Med Biol Res. 2003, 36(4):403-8.
63. She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 2005, 8(4):287-97.
64. Xiao D, Singh SV. Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells. Carcinogenesis. 2006, 27(3):533-40.
65. Adachi M, Zhang YB, Imai K. Mutation of BAD within the BH3 domain impairs its phosphorylation-mediated regulation. FEBS Lett. 2003, 551(1-3):147-52.
66. Subramanian RR, Masters SC, Zhang H, Fu H. Functional conservation of 14-3-3 isoforms in inhibiting bad-induced apoptosis. Exp Cell Res. 2001,271(1):142-51.
67. Arimoto-Ishida E, Ohmichi M, Mabuchi S, Takahashi T, Ohshima C, Hayakawa J, Kimura A, Takahashi K, Nishio Y, Sakata M, Kurachi H, Tasaka K, Murata Y. Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin. Endocrinology. 2004, 145(4):2014-22.
68. Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003,11(1):11-23.
69. Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel JT, McShea A, Hermeking H, Funk JO. The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax. J Biol Chem. 2001, 276(48):45201-6.
70. Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 2004, 23(8):1889-99.
71. Zhang P, Chan SL, Fu W, Mendoza M, Mattson MP. TERT suppresses apoptotis at a premitochondrial step by a mechanism requiring reverse transcriptase activity and 14-3-3 protein-binding ability. FASEB J. 2003,17(6):767-9.
72. Heyninck K, Van Huffel S, Kreike M, Beyaert R. Yeast two-hybrid screening for proteins interacting with the anti-apoptotic protein A20. Methods Mol Biol. 2004,282:223-41.
73. Tzivion G, Shen YH, Zhu J. 14-3-3 proteins; bringing new definitions to scaffolding. Oncogene. 2001, 20(44):6331-8.
74. Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AE, Yaffe MB. MAPKAPkinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell. 2005, 17(1):37-48.
75. J. Y. Toshima,J. Toshima,T. Watanabe,et al. Binding of 14-3-3βregulates the kinase activity and subcellular localization of testicular protein kinase1 [J].J Biol Chem,2001,276(46): 43471-43481.
76. Y. Wang,C.Jacobs,KE.Hook,et al.Binding of 14-3-3β to the carboxyl terminus of Wee1 increases Wee1 stability,kinase activity,and G2-M cell population [J].Cell Growth Differ,2000,11(4):211-219.
77. Takihara Y,atsuda Y,Hara J.Role of the β isoform of 14-3-3 proteins in cellular proliferation and oncogenic transformation [J].Carcinogenesis,2000,21(11):2073-2077.
78. Sugiyama A,Miyagi Y,Komiya Y,et al.Forced expression of antisense 14-3-3β RNA suppresses tumor cell growth in vitro and in vivo [J].Carcinogenesis,2003, 24(9):1549-1559.
79. M. Wanzel, D. Kleine-Kohlbrecher, S. Herold, Akt and 14-3-3eta regulate Miz1 to control cell-cycle arrest after DNA damage, Nat Cell Biol. 7(2005)30-41.
80. J. Won, D.Y. Kim, M. La, D. Kim, G.G. Meadows, C.O. Joe, Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis, J. Biol. Chem. 278 (2003) 19347–19351.
81. J. Sunayama, F. Tsuruta, N. Masuyama, Y. Gotoh, JNK antagonizes Akt mediated survival signals by phosphorylating 14-3-3, J. Cell Biol. 170 (2005) 295–304.
82. Chatterjee D,Goldman M,Braastad CD,Darnowski J,Wyche JH,Pantazis P,Goodglick L. Reduction of 9-nitrocamptothecin-triggeraed apoptosis in Du-145 human prostate cancer cells by ectopic expression of 14-3-3zeta. Int J Oncol.2004,25(2):503-9.
83. Zhu P, Sun Y, Xu R, Sang Y, Zhao J, Liu G, Cai L, Li C, Zhao S. Theinteraction between ADAM 22 and 14-3-3zeta: regulation of cell adhesion and spreading. Biochem Biophys Res Commun. 2003,21; 301 (4):991-9.
84. 曹卫东,章翔,张剑宁等.14-3-3 蛋白在星形细胞瘤中的表达及意义[J].中华神经外科疾病研究杂志,2007,6(2):141-145.
2. van Heusden GP. 14-3-3 proteins: regulators of numerous eukaryotic proteins. IUBMB Life. 2005, 57(9):623-9.
3. Darling DL, Yingling J, Wynshaw-Boris A. Role of 14-3-3 proteins in eukaryotic signaling and development. Curr Top Dev Biol. 2005, 68:281-315.
4. Bridges D, Moorhead GB. 14-3-3 proteins: a number of functions for a numbered protein. Sci STKE. 2005, 2005(296):re10.
5. Mhawech P. 14-3-3 proteins--an update. Cell Res. 2005, 15(4):228-36.
6. Muslin AJ, Lau JM. Differential functions of 14-3-3 isoforms in vertebrate development. Curr Top Dev Biol. 2005, 65:211-28.
7. Wilker E, Yaffe MB. 14-3-3 Proteins--a focus on cancer and human disease. J Mol Cell Cardiol. 2004, 37(3):633-42.
8. Mackintosh C. Dynamic interactions between 14-3-3 proteins and phosphoproteins regulate diverse cellular processes. Biochem J. 2004, 381(Pt 2):329-42.
9. Dougherty MK, Morrison DK. Unlocking the code of 14-3-3. J Cell Sci. 2004, 117(Pt 10):1875-84.
10. Hermeking H. The 14-3-3 cancer connection. Nat Rev Cancer. 2003, 3(12):931-43.
11. Siles-Lucas Mdel M, Gottstein B. The 14-3-3 protein: a key molecule in parasites as in other organisms. Trends Parasitol. 2003 Dec;19(12):575-81.
12. Sehnke PC, DeLille JM, Ferl RJ. Consummating signal transduction: the role of 14-3-3 proteins in the completion of signal-induced transitions in protein activity. Plant Cell. 2002,14 Suppl:S339-54.
13. Reuther GW, Pendergast AM. The roles of 14-3-3 proteins in signal transduction. Vitam Horm. 1996, 149-75.
14. Xing H, Zhang S, Weinheimer C, Kovacs A, Muslin AJ. 14-3-3 proteinsblock apoptosis and differentially regulate MAPK cascades. EMBO J. 2000;19: 349–358.
15. Takahashi Y. The 14-3-3 proteins: gene, gene expression, and function. Neurochem Res. 2003, 28(8):1265-73.
16. Fu H, Subramanian RR, Masters SC. 14-3-3 proteins: structure, function, and regulation. Annu Rev Pharmacol Toxicol. 2000,40:617-47.
17. Aitken A. Functional specificity in 14-3-3 isoform interactions through dimer formation and phosphorylation. Chromosome location of mammalian isoforms and variants. Plant Mol Biol. 2002,50(6):993-1010.
18. Roberts MR. 14-3-3 proteins find new partners in plant cell signalling. Trends Plant Sci. 2003, 8(5):218-23.
19. van Hemert MJ, van Heusden GP, Steensma HY. Yeast 14-3-3 proteins. Yeast. 2001,18(10):889-95.
20. Berg D, Holzmann C, Riess O. 14-3-3 proteins in the nervous system. Nat Rev Neurosci. 2003, 4(9):752-62.
21. Skoulakis EM, Davis RL. 14-3-3 proteins in neuronal development and function. Mol Neurobiol. 1998, 16(3):269-84.
22. Boston PF, Jackson P, Kynoch PAM, Thompson RJ. Purification, properties, and immunohistochemical localisation of human brain 14-3-3 protein. J Neurochem. 1982;38:1466–1474
23. Baxter HC, Liu WG, Forster JL, Aitken A, Fraser JR. Immunolocalisation of 14-3-3 isoforms in normal and scrapie-infected murine brain. Neuroscience. 2002,109(1):5-14.
24. Eckardt NA. Transcription factors dial 14-3-3 for nuclear shuttle. Plant Cell. 2001,13(11):2385-9.
25. Muslin AJ, Xing H. 14-3-3 proteins: regulation of subcellular localization by molecular interference. Cell Signal. 2000,12(11-12):703-9.
26. Wang H, Zhang L, Liddington R, Fu H. Mutations in the hydrophobic surface of an amphipathic groove of 14-3-3 zeta disrupt its interaction with Raf-1 kinase [J]. J Biol Chem, 1998, 273(26): 16297-16304.
27. Liu D, Bienkowska J, Petosa C ,et al. Crystal structure of the zeta isoform of the 14-3-3 protein [J]. Nature, 1995, 376(6536): 191-194.
28. Petosa C, Masters SC, Bankston LA, et al. 14-3-3 zeta binds a phosphorylated Raf peptide and an unphosphorylated peptide via its conserved amphipathic groove [J]. J Biol Chem., 1998, 273(26): 16305-16310.
29. Konishi Y,Lehtinen M,Donovan N,et al. CDC2 phosphorylation of BAD links the cell cycle to the cell death machinery [J].Mol Cell,2002,9(5):1005-1016.
30. Nomura M,Shimizu S,Sugiyama T,et al.14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax[J].J Biol Chem,2003,278(3):2058-2065.
31. Brunet A, Bonni A, Zigmond MJ, et a1.Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor [J].Cell,1999,96(6):857-868.
32. Wang HG, Rapp UR, Reed JC. Bcl-2 targets the protein kinase Raf-1 to mitochondria [J]. Cell, 1996, 87(4): 629-638.
33. Wilker E, Yaffe MB.14-3-3 proteins-a focus on cancer and human disease [J]. J Mol Cell Cardiol,2004,37(3): 633-642.
34. Dougherty MK, Morrison DK. Unlocking the code of 14-3-3[J].J Cell Sci,2004, 117(Pt10): 1875-1884.
35. Hermeking H. The 14-3-3 cancer connection [J].Nat Rev Cancer,2003, 3(12): 931-43.
36. Suzuki H, Itoh F, Toyota M, et a1. Inactivation of the 14-3-3 sigma gene is associated with 5' CpG island hypermethylation in human cancers [J]. Cancer Res, 2000, 60(16): 4353-4357.
37. Hermeking H, Lengauer C, Polyak K, et al. 14-3-3 sigma is a p53-regulated inhibitor of G2/M progression [J]. Mol Cell, 1997, 1(1):3-11.
38. Chan TA, Hermeking H, Lengauer C, et al.14-3-3σ is required to prevent mitotic catastrophe after DNA damage [J]. Nature, 1999, 401(6753): 616-620.
39. Nacht M, Ferguson AT, Zhang W, et al. Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer [J]. Cancer Res, 1999, 59(21): 5464-5470.
40. Ferguson AT, Evron E, Umbricht CB, et al. High frequency of hypermethylation at the 14-3-3σ locus leads to gene silencing in breast cancer [J]. Proc Natl Acad Sci USA, 2000, 97(11): 6049-6054.
41. Lodygin D, Hermeking H. The role of epigenetic inactivation of
14-3-3sigma in human cancer [J]. Cell Research, 2005, 15(4): 237-246.
42. Qi W, Liu X, Qiao D, Martinez JD. Isoform-specific expression of 14-3-3 proteins in human lung cancer tissues [J].Int J Cancer, 2005, 113(3): 359-363.
43. Takihara Y, Matsuda Y, Hara J. Role of the β-isoform of 14-3-3 proteins in cellular proliferation and oncogenic transformation [J]. Carcinogenesis,2000,21(11): 2073-2077.
44. Sugiyama A, Miyaqi Y, Komiya Y, et al. Forced expression of antisense
14-3-3β RNA suppresses tumor cell growth in vitro and in vivo [J]. Carcinogenesis, 2003,24(9): 1549-1559.
45. Martin D, Brown-Luedi M, Chiquet-Ehrismann R. Tenascin-C signaling through induction of 14-3-3tau [J]. J Cell Biol,2003,160(2):171-175.
46. Villaret DB, Wang T, Dillon D, et al. Identification of genes overexpressed in head and neck squamous cell carcinoma using a combination of complementary DNA subtraction and microarray analysis [J]. Laryngoscope,2000,110(3 Pt 1):374-381.
47. Masters SC, Fu H.14-3-3 proteins mediate an essential anti-apoptotic signal [J].J Biol Chem,2001,276(48):45193-45200.
48. Graves PR, Yu L, Schwarz JK, et al. The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01 [J]. J Biol Chem, 2000,275(8):5600-5605.
49. 章翔, 主编. 神经系统肿瘤学. 北京: 军事医学科学出版社, 1999, 1-35.
50. Sanson M, Thillet J, Hoang-Xuan K. Molecular changes in gliomas. Curr Opin Oncol, 2004, 16(6): 607-613.
51. 张冠中, 肖龙海, 李新钢. 胶质瘤凋亡研究进展. 河北医学. 2004, 10(2): 184-186.
52. Boston PF, Jackson P, Kynoch PAM, Thompson RJ. Purification, properties, and immunohistochemical localisation of human brain 14-3-3 protein. JNeurochem. 1982,38:1466–1474
53. Boston PF, Jackson P, Thompson RJ. Human 14-3-3 protein: radioimmunoassay, tissue distribution, and cerebrospinal fluid levels in patients with neurological disorders. J Neurochem. 1982,38:1475–1482.
54. Kawamoto Y, Akiguchi I, Nakamura S, Honjyo Y, Shibasaki H, Budka H. 14-3-3 proteins in Lewy bodies in Parkinson disease and diffuse Lewy body disease brains. J Neuropathol Exp Neurol. 2002,61:245–253.
55. Kawamoto Y, Akiguchi I, Nakamura S, Budka H. Accumulation of 14-3-3 proteins in glial cytoplasmic inclusions in multiple system atrophy. Ann Neurol. 2002,52:722–731.
56. Kawamoto Y, Akiguchi I, Kovacs GG, Flicker H, Budka H. Increased 14-3-3 immunoreactivity in glial elements in patients with multiple sclerosis. Acta Neuropathol (Berl). 2004,107:137-143.
57. Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature, 2001, 411(6835): 342-348.
58. Okada H, Mak TW. Pathways of apoptotic and non-apoptotic death in tumour cells. Nat Rev Cancer, 2004, 4(8): 592-603.
59. Cheung HH, Arora V, Korneluk RG. Abnormalities of cell structures in tumors: apoptosis in tumors.EXS. 2006, 96:201-21.
60. Staunton MJ, Gaffney EF. Apoptosis: basic concepts and potential significance in human cancer.Arch Pathol Lab Med. 1998 ,122(4):310-9.
61. Rudin CM, Thompson CB: Apoptosis and disease: regulation and clinical relevance of programmed cell death. Annu Rev Med. 1997;48:267–281.
62. Rosenquist M. 14-3-3 proteins in apoptosis. Braz J Med Biol Res. 2003, 36(4):403-8.
63. She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N. The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 2005, 8(4):287-97.
64. Xiao D, Singh SV. Diallyl trisulfide, a constituent of processed garlic, inactivates Akt to trigger mitochondrial translocation of BAD and caspase-mediated apoptosis in human prostate cancer cells. Carcinogenesis. 2006, 27(3):533-40.
65. Adachi M, Zhang YB, Imai K. Mutation of BAD within the BH3 domain impairs its phosphorylation-mediated regulation. FEBS Lett. 2003, 551(1-3):147-52.
66. Subramanian RR, Masters SC, Zhang H, Fu H. Functional conservation of 14-3-3 isoforms in inhibiting bad-induced apoptosis. Exp Cell Res. 2001,271(1):142-51.
67. Arimoto-Ishida E, Ohmichi M, Mabuchi S, Takahashi T, Ohshima C, Hayakawa J, Kimura A, Takahashi K, Nishio Y, Sakata M, Kurachi H, Tasaka K, Murata Y. Inhibition of phosphorylation of a forkhead transcription factor sensitizes human ovarian cancer cells to cisplatin. Endocrinology. 2004, 145(4):2014-22.
68. Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003,11(1):11-23.
69. Samuel T, Weber HO, Rauch P, Verdoodt B, Eppel JT, McShea A, Hermeking H, Funk JO. The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax. J Biol Chem. 2001, 276(48):45201-6.
70. Tsuruta F, Sunayama J, Mori Y, Hattori S, Shimizu S, Tsujimoto Y, Yoshioka K, Masuyama N, Gotoh Y. JNK promotes Bax translocation to mitochondria through phosphorylation of 14-3-3 proteins. EMBO J. 2004, 23(8):1889-99.
71. Zhang P, Chan SL, Fu W, Mendoza M, Mattson MP. TERT suppresses apoptotis at a premitochondrial step by a mechanism requiring reverse transcriptase activity and 14-3-3 protein-binding ability. FASEB J. 2003,17(6):767-9.
72. Heyninck K, Van Huffel S, Kreike M, Beyaert R. Yeast two-hybrid screening for proteins interacting with the anti-apoptotic protein A20. Methods Mol Biol. 2004,282:223-41.
73. Tzivion G, Shen YH, Zhu J. 14-3-3 proteins; bringing new definitions to scaffolding. Oncogene. 2001, 20(44):6331-8.
74. Manke IA, Nguyen A, Lim D, Stewart MQ, Elia AE, Yaffe MB. MAPKAPkinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. Mol Cell. 2005, 17(1):37-48.
75. J. Y. Toshima,J. Toshima,T. Watanabe,et al. Binding of 14-3-3βregulates the kinase activity and subcellular localization of testicular protein kinase1 [J].J Biol Chem,2001,276(46): 43471-43481.
76. Y. Wang,C.Jacobs,KE.Hook,et al.Binding of 14-3-3β to the carboxyl terminus of Wee1 increases Wee1 stability,kinase activity,and G2-M cell population [J].Cell Growth Differ,2000,11(4):211-219.
77. Takihara Y,atsuda Y,Hara J.Role of the β isoform of 14-3-3 proteins in cellular proliferation and oncogenic transformation [J].Carcinogenesis,2000,21(11):2073-2077.
78. Sugiyama A,Miyagi Y,Komiya Y,et al.Forced expression of antisense 14-3-3β RNA suppresses tumor cell growth in vitro and in vivo [J].Carcinogenesis,2003, 24(9):1549-1559.
79. M. Wanzel, D. Kleine-Kohlbrecher, S. Herold, Akt and 14-3-3eta regulate Miz1 to control cell-cycle arrest after DNA damage, Nat Cell Biol. 7(2005)30-41.
80. J. Won, D.Y. Kim, M. La, D. Kim, G.G. Meadows, C.O. Joe, Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis, J. Biol. Chem. 278 (2003) 19347–19351.
81. J. Sunayama, F. Tsuruta, N. Masuyama, Y. Gotoh, JNK antagonizes Akt mediated survival signals by phosphorylating 14-3-3, J. Cell Biol. 170 (2005) 295–304.
82. Chatterjee D,Goldman M,Braastad CD,Darnowski J,Wyche JH,Pantazis P,Goodglick L. Reduction of 9-nitrocamptothecin-triggeraed apoptosis in Du-145 human prostate cancer cells by ectopic expression of 14-3-3zeta. Int J Oncol.2004,25(2):503-9.
83. Zhu P, Sun Y, Xu R, Sang Y, Zhao J, Liu G, Cai L, Li C, Zhao S. Theinteraction between ADAM 22 and 14-3-3zeta: regulation of cell adhesion and spreading. Biochem Biophys Res Commun. 2003,21; 301 (4):991-9.
84. 曹卫东,章翔,张剑宁等.14-3-3 蛋白在星形细胞瘤中的表达及意义[J].中华神经外科疾病研究杂志,2007,6(2):141-145.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |