人肺腺癌细胞TGF-β1对细胞凋亡调控的实验研究
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摘要
转化生长因子β1(TGF-β1)属于生长因子超家族,其生物学效应非常广泛,主要包括调节细胞增殖和分化、参与胚胎发育调节、促进细胞外基质(ECM)形成和抑制免疫反应等。TGF-β1在包括肺癌在内的多种恶性肿瘤细胞中常呈高表达,并可由癌旁基质细胞产生。目前认为,在肿瘤早期TGF-β1抑制原癌基因c-myc等,阻止细胞生长周期从G1期进入S期;而在肿瘤的中晚期(肿瘤浸润血管逐渐开始形成),TGF-β1可通过促进血管生成、肿瘤细胞迁移、免疫抑制等途径为肿瘤的生长、浸润及转移提供适宜的微环境,使肿瘤细胞表现恶性特征。对非肿瘤细胞的观察发现,TGF-β1对细胞中Fas/FasL蛋白表达具有调控作用。Fas/FasL为重要的细胞凋亡途径,在非肿瘤细胞中TGF-β1通过上调Fas表达,从而激活Fas/FasL凋亡信息链中的凋亡蛋白酶caspase家族诱导细胞发生凋亡。另外,TGF-β1与细胞内TGF-β1受体结合后,亦能通过下游信号smad蛋白激活caspase家族引起细胞凋亡。因此,TGF-β1可看作是一个诱导细胞凋亡的细胞因子,在机体内发挥清除异常细胞的重要作用。但TGF-β1与肿瘤细胞凋亡的关系尚不明确,目前国内外鲜有肿瘤细胞中TGF-β1与Fas/FasL凋亡信号通路之间关系的研究报道。
为探讨TGF-β1与肿瘤细胞凋亡的关系,本实验按如下三个部份进行研究。第一部分通过siRNA靶点序列设计软件结合Angela siRNA设计原则,设计、合成TGF-β1特异性siRNA靶点序列;再将靶点序列插入PAVU6+27质粒构建siRNA质粒;通过免疫荧光、免疫印记等方法检测转染siRNA质粒后人A549肺癌细胞株中TGF-β1的表达水平。第二部分将TGF-β1特异性小干扰RNA质粒pOligo1216和无关对照质粒pOligo Control转染肺腺癌A549细胞,检测TGF-β1 siRNA质粒转染后(即TGF-β1被静默后),上述A549细胞中Fas/FasL分子表达与凋亡酶caspase-3、caspase-8的活性;然后通过蛋白转染剂,将TGF-β1蛋白导入A549细胞,检测细胞内TGF-β1蛋白上调后细胞中Fas/FasL分子表达与凋亡酶caspase-3、caspase-8的活性,以了解TGF-β1对人肺腺癌细胞Fas/FasL凋亡通路的影响。第三部分参照Saitoh、Crowley等学者所报告的方法,首先检测人肺腺癌A549细胞与Calu-6细胞的HLA-ABDR等位基因,再构建稳定表达HLA-A2的人肺腺癌细胞系,通过混合淋巴细胞肿瘤细胞培养(MLTC)的方法,对诱导刺激健康人PBL产生肺癌特异性CTL作了初步的研究与探索。
TGF-β_1 belongs to super family of growth factor and its biological effect is very common including regulation of cell proliferation and differentiation, regulation of embryonic development, enhancement of ECM formation and suppression of immune- system. TGF-β_1 is highly expressed in many malignant tumor cells including lung cancer cells and it can be expressed in matrix cells around cancer cells. In current opinion, TGF-β1 suppresses proto-oncogene such as c-myc to inhibit cell growth cycle of G1 stage to S stage.But in the middle or later stage of cancer when the tumor infiltrating blood vessels has been forming, TGF-β1 can make tumor cells be of much maliganancy by stimulation of tumor infiltrating blood vessls, by enhancement of cell migration and by immune suppressing.So the microenvironment of growth, infiltration and metastasis for cancer cells is forming. According to the results of observation in normal cells, TGF-β1 can regulate Fas/FasL. Fas/FasL system is a very important apopatosis pathway. In normal cells, TGF-β_1 can upregulat Fas, so that caspases in Fas/FasL pathway are activated to induce cell apoptosis. Moreover, caspases can be activated by combination of Fas with FasL. So TGF-β_1 can be regarded as an important factor that induces apoptosis and plays the role of abnormal cell clearance.But the relationship between TGF-β1 and cancer cell apoptosis is not very clear yet. The experimental report on it is very scarce.
In order to study the relationship of TGF-β_1 and cancer apoptosis,the experiment develops according to three steps: step1,siRNA target sequences were analysed and synthesized by siRNA design software plus Angela siRNA principle.Then siRNA vehicle was reformed by the inserting of siRNA target sequences to PAVU6+27. Expressing Level of TGF-β_1 was analysed with indirect immunofluorescence and western blotting after siRNA vehicles were transfected into A549 cells. Step2, the expression level of Fas/FasL and activity of caspase-3/caspase-8 was detected in A549 cells that had been transfected with pOligo1216 or pOligo Control. Then the expression level of Fas/FasL and activity of
为探讨TGF-β1与肿瘤细胞凋亡的关系,本实验按如下三个部份进行研究。第一部分通过siRNA靶点序列设计软件结合Angela siRNA设计原则,设计、合成TGF-β1特异性siRNA靶点序列;再将靶点序列插入PAVU6+27质粒构建siRNA质粒;通过免疫荧光、免疫印记等方法检测转染siRNA质粒后人A549肺癌细胞株中TGF-β1的表达水平。第二部分将TGF-β1特异性小干扰RNA质粒pOligo1216和无关对照质粒pOligo Control转染肺腺癌A549细胞,检测TGF-β1 siRNA质粒转染后(即TGF-β1被静默后),上述A549细胞中Fas/FasL分子表达与凋亡酶caspase-3、caspase-8的活性;然后通过蛋白转染剂,将TGF-β1蛋白导入A549细胞,检测细胞内TGF-β1蛋白上调后细胞中Fas/FasL分子表达与凋亡酶caspase-3、caspase-8的活性,以了解TGF-β1对人肺腺癌细胞Fas/FasL凋亡通路的影响。第三部分参照Saitoh、Crowley等学者所报告的方法,首先检测人肺腺癌A549细胞与Calu-6细胞的HLA-ABDR等位基因,再构建稳定表达HLA-A2的人肺腺癌细胞系,通过混合淋巴细胞肿瘤细胞培养(MLTC)的方法,对诱导刺激健康人PBL产生肺癌特异性CTL作了初步的研究与探索。
TGF-β_1 belongs to super family of growth factor and its biological effect is very common including regulation of cell proliferation and differentiation, regulation of embryonic development, enhancement of ECM formation and suppression of immune- system. TGF-β_1 is highly expressed in many malignant tumor cells including lung cancer cells and it can be expressed in matrix cells around cancer cells. In current opinion, TGF-β1 suppresses proto-oncogene such as c-myc to inhibit cell growth cycle of G1 stage to S stage.But in the middle or later stage of cancer when the tumor infiltrating blood vessels has been forming, TGF-β1 can make tumor cells be of much maliganancy by stimulation of tumor infiltrating blood vessls, by enhancement of cell migration and by immune suppressing.So the microenvironment of growth, infiltration and metastasis for cancer cells is forming. According to the results of observation in normal cells, TGF-β1 can regulate Fas/FasL. Fas/FasL system is a very important apopatosis pathway. In normal cells, TGF-β_1 can upregulat Fas, so that caspases in Fas/FasL pathway are activated to induce cell apoptosis. Moreover, caspases can be activated by combination of Fas with FasL. So TGF-β_1 can be regarded as an important factor that induces apoptosis and plays the role of abnormal cell clearance.But the relationship between TGF-β1 and cancer cell apoptosis is not very clear yet. The experimental report on it is very scarce.
In order to study the relationship of TGF-β_1 and cancer apoptosis,the experiment develops according to three steps: step1,siRNA target sequences were analysed and synthesized by siRNA design software plus Angela siRNA principle.Then siRNA vehicle was reformed by the inserting of siRNA target sequences to PAVU6+27. Expressing Level of TGF-β_1 was analysed with indirect immunofluorescence and western blotting after siRNA vehicles were transfected into A549 cells. Step2, the expression level of Fas/FasL and activity of caspase-3/caspase-8 was detected in A549 cells that had been transfected with pOligo1216 or pOligo Control. Then the expression level of Fas/FasL and activity of
引文
1. Abrahams V, Straszewski S, Kamsteeg M, et al. Epithelial ovarian cancer cells secrete functional Fas ligand. Cancer Res,2003,63(12):5573-5581.
2. Yu J, Lee P, Ehtesham M, et al. Intratumoral T cell subset ratios and Fas ligand expression on brain tumor endothelium. J Neurooncol, 2003,64(3):55-61.
3. Kim H, Lee S, Lee J, et al. Mutational analysis of Fas ligand gene in human non-Hodgkin lymphoma. APMIS, 2003,111(10):490-496.
4. Jian-Jun Chen, Yongnian S, Gary J, et al. Regulation of the Pro inflammatory Effects of Fas Ligand (CD95L). SCIENCE, 1998 , 282(10) :1714-1716.
5. Velasco J, Arici A, Zreik T, et al. Macrophage derived growth factors modulate Fas ligand expression in cultured endometrial stromal cells: a role in endometriosis. Mol Hum Reprod,1999,5(8):642-650.
6. Craig D, Crystal B, Corneliu N, et al. Activation of a caspase-dependent oxidative damage response mediates TGF β 1 apoptosis in rat hepatocytes. Experimental and Molecular Pathology,2003,74(4):256–261.
7. Yuan Z, Barbara A, Elke B,et al. TGF-b1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures. Neurochemistry International,2001,38(3): 227– 235.
8. Barna G, Sebestyen A, Chinopoulos C,et al. TGF β 1 kills lymphoma cells using mitochondrial apoptotic pathway with the help of caspase-8. Hepatology,1999,30(11):1215-1222.
9. Laurent G, Shailaja K, Thomas B, et al. Transforming Growth Factor β 1 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc. J. Exp. Med,1999,189(7):231–239.
10. Jung YJ. TGF-β1 inhibits Fas-mediated apoptosis by regulating surface Fas and cFLIPL expression in human leukaemia/lymphoma cells. Int J Mol Med. 2004, 13(1):99-104.
11. Gemma A , Uematsu K, Hagiwara K, et al . Mechanism of resistance to growth inhibition by transforming growth factor2beta 1 ( TGF-beta 1) in primary lung cancer and new molecular targets in therapy. Gan To Kagaku Ryoho, 2000 , 27(10) :1253-1259.
12. Pasche B. Role of TGF-βin cancer. J Cell Physiol , 2001,186(2): 153-168.
13. Barna G, Sebestyen A, Chinopoulos C,et al. TGF-β 1 kills lymphoma cells using mitochondrial apoptotic pathway with the help of caspase-8. Hepatology,1999,30(12):1215-1222.
14. Paul CP, Good PD, Winer I ,et al. Effective expression of small interfering RNA in human cells. Nat Biotechnol, 2002,20(5):505-508.
15. Elbashir SM, Harborth j, Lendeckel W, et al . Duplexes of 21-nucleotide RNAs mediate RNA Interference in cultured mammalian cells. Nature, 2001, 411(11): 494-498.
16. Kapadia SB, Brideau-Andersen A, Chisari FV. Interference of hepatitis C virus RNA replication by short interfering RNAs. Proc Natl Acad Sci U S A. 2003,100 (20): 2014- 2018
17. Castanotto D, Li H, Rossi JJ. Functional siRNA expression from transfected PCR products. RNA,2002,8(15): 1454-1460.
18. Paul CP, Good PD, Winer I ,et al. Effective expression of small interfering RNA in human cells. Nat Biotechnol, 2002,20(5):505-508.
19. McCaffrey AP, Nakai H, Pandey K,et al. Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol, 2003, 21(5):639-644.
20. Angela R, Devin L, Queta B, et al. Rational siRNA design for RNA interference. Nat Biotechnol,2004, 22(10): 326-330.
21. 羊正纲,陈智,徐宁,等.载体法筛选乙型肝炎病毒S基因小干扰RNA靶位体系的建立.中华肝脏病杂志,2004,12(4):515-518.
22. 蹇锐,程小星,安静,等.应用载体介导的RNAi技术抑制Bcl-2的表达.第三军医大学学报,2004,4(5):294-297.
23. J.萨姆布鲁克,E.F.弗里奇,T.曼尼阿蒂斯,等.分子克隆实验指南.第二版.北京:科学技术出版社,1992.63-69
24. Schroter M, Peli J, Hahne M, et al. Fas-dependent tissue turnover is implicated in tumor cell clearance. Oncogene, 2000,19(14): 1794-1800.
25. Blobe GC.Schiemarm .Lodish I-IF.Role of transforming growth factor in human disease.N Engl J Med,2000,342(18):1350-1358.
26. Suzuki H,Yagi K,Kondo M ,et a1.C-skj inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements.Oncogene, 2004, 23(29): 5068-5076.
27. Shi Y,Massague J.Mechanisms of TGF-βsignaling from cell membrane to the nucleus.Cell,2003,113(14):685-67O.
28. Liu C,Gaca M D,Swenson ES,et a1.Smads 2 and 3 are differentially activated by transforming growth actor-beta (TGF-beta)in quiescent and activated hepatic stellate cells . Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent.J Biol Chem,2003,278(13):11721-11728.
29. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer : a phase Ⅲ trial-INTACT 1.J Clin Oncol.2004, 22(5):777-784.
30. Nukaya I , Yasumoto M, Iwasaki T, et al. Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer, 1999, 80(1) :92-97.
31. Crowley NJ , Slingluff CL , Darrow TL , et al. Generation of human autologous melanoma specific cytotoxic T cells using HLA-A2-matched allogeneic melanomas. Cancer Res, 1990, 50(4) :492-498.
32. Stevens EJ , Jacknin L , Robbins PF , et al . Generation of tumor-specific CTLs from melanoma patients by using peripheral blood stimulated with allogeneic melanoma tumor cell lines. Fine specificity and MART21 melanoma antigen recognition , J Immunol , 1995 , 154(8) :762-771.
33. 冯明亮,季 芸,陆 琼,等.江浙沪地区汉族人群 HLA单体型研究.遗传学报,2003, 30(6): 584-588.
34. Trojan A, Schultze J, Witzens M., et al. Immunoglobulin framework derived peptides function as cytotoxic T-cell epitopes commonly expressed in B-cell malignancies. Nat Med, 2000, 6(4):667–672.
35. Maleno I , Cabrera T, Salinero J , et al . Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas : high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunol Immunother,2002,51(4) : 389-396.
36. Rimmelzwaan G.F, Boon A.C, Geelhoed-Mieras M.M, et al. Human airway epithelial cells present antigen to influenza virus-specific CD8+ CTL inefficiently after incubation with viral protein together with ISCOMATRIX. Vaccine, 2004,22 (6): 2769–2775.
37. Hanagiri T, Yoshino I, Takenoyama M, et al. Effects of interleukin-12 on the induction of cytotoxic T lymphocytes from the regional lymph node lymphocytes of patients with lung adenocarcinoma. Jpn J Cancer Res, 1998,89(2):192-198.
38. Peltenburg LT, Dee R,Schrier PI. Down regulation of HLA class I expression by c-myc in human melanoma is independent of enhancer A. Nucleic Acids Research, 1993, 21(5): 1179-1185.
39. Minzhen X , Qiu G , Jing Z , et a1 . Genetic modulation of tumor antigen presentation.Trends in Blotethnology, 2000, 18(4):167-173.
40. Rosenberg S.Progress in human tumor immunology and immunotherapy.Nature, 2001,41l(4):380-385.
41. Nukaya I , Yasumoto M, Iwasaki T, et al. Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer, 1999 , 80(1) :92-97.
42. Cedrik MB, Ralf G.M, Thomas W, et al. The use of HLA-A*0201-transfected K562 as standard antigen-presenting cells for CD8+T lymphocytes in IFN-γ ELISPOT assays. Journal of Immunological Methods, 2002, 259(1): 95-110.
43. Peltenburg LT, Dee R,Schrier PI. Down regulation of HLA class I expression by c-myc in human melanoma is independent of enhancer A. Nucleic Acids Research, 1993, 21(5): 1179-1185.
44. Maleno I , Cabrera T, Salinero J , et al . Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas : high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunol Immunother , 2002 , 51(4) : 389-396.
45. Nukaya I , Yasumoto M, Iwasaki T, et al. Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer, 1999 , 80(1) :92-97.
46. De Visser K E, Schumacher T N, Kruisbeek Am, et al. CD8+ T cell tolerance and cancer immunotherapy[J]. J Immunother,2003,26(1):1-11.
47. 徐文华,王鈜,孙立荣,等. 重组人粒细胞集落刺激因子对 HL-60 细胞影响的研究. 医学分子生物学杂志,2005,2(3):178-180.
48. De Visser K E, Schumacher T N, Kruisbeek Am, et al. CD8+ T cell tolerance and cancerimmunotherapy. J Immunother,2003,26(1):1-11.
49. Saitoh S , Kurisaka M, Mosi K, et al . Induction of specific cytotoxic T lymphocytes against autologous brain tumor by cross reactive allotumor cell stimulation. Jpn J Cancer Res , 1997 , 88(3) :289-295.
50. Kikuchi T,Akasaki Y,Joki T,et a1.Antitumor activity of interleukir-18 on mouse glioma cells.J Immunother,2000,23(2):184-189.
51. Castelli C, Rivoltini L, Rini F, et al. Heat shock proteins: biological functions and clinical application as personalized vaccines for human cancer. Cancer Immunol Immunother, 2004,53(3):227-23.
52. Wood C M, Goodman P A, Vassilev, A O, et al. CD95(APO-1/CD95)deficiency in infant acute lymphoblastic leukemia: detection of novel soluble Fas splice variants. Eur J Haematol,2003,70(2):156-171.
53. Julie AM,James JK,Vivian M,et al.Invasion and metastasis of a mammary tumor involves TGF-βsignaling.Int J Cancer,2001,91(1):762-821.
54. Roberts H ,Anderson E ,James RD ,et al.Transforming growth factor in patients with colorectal cancer:association with disease progression. Gastroenterology,1996,110(2):2752-2791.
55. Wang J ,Sun L ,Myeraff LL ,et al . Demonstration that mutation of the type ⅡTGF-βreceptor error positive colon carcinoma cells.J Biol Chem,1995,270(199): 22044-220491.
56. Laure GA ,Souza RF ,Vellucci VF ,et al .Loss of transforming growth factor beat type Ⅱ receptor gene expression in primary human esophageal cancer.Lab Invest,1996,75(2):2632-2721.
57. Tanaks S ,Mori M,Mafune K,et al.A dominant negative mutation growth factor beta receptor typeⅡgene in microsatellite stable oesophageal carcinoma.Br J Cancer, 2000,82(9):15572-15601.
58. Laure GA ,Souza RF ,Vellucci VF ,et al .Loss of transforming growth factor beat type Ⅱ receptor gene expression in primary human esophageal cancer.Lab Invest,1996,75(2):2632-2721.
59. Marx J. DNA repair defect tied to mutated TGF- β receptor gene.Science,1995,268(5215) :12762-12801.
60. Johannsdottir JT,Jonasson TG,Bergthorosson JJ ,et al . The effect of mismatch repair deficiency on tumourigenesis;microsatellite instability affecting genes containing short repeated sequences.Int Oncol ,2000 ,16(1):1332-1391.
61. Gebert J,Sun M,Ridder R ,et al .Molecular profiling of sporadic colorectal tumors by microsatellite analysis.Int J Oncol,2000,16(1) :1692-1791.
62. Han HJ ,Yanagisawa A ,Kato Y,et al . Genetic instibity in pancreatic cancer and pooly differentiated type of gastric cancer.Cancer Res,1993,53 (21):50872-50891.
63. Yamashita K,Arimura Y,Kurokawa S ,et al .Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract.Gut,2000,46(6):7902-7941.
64. Gonzalez-Zulueta M,Ruppert JM,Tokino K,et al.Microsatellite instability In bladder cancer.Cancer Res,1993,53(23):56202-56231.
65. Myeroff LL,Parsons R ,Kim SJ ,et al . A transforming growth factorβreceptor type Ⅱgene mutation common in colon and gastric but rare in endome trial cancers with microsatellite instability.Cancer Res ,1995 ,55 (23):55452-55471.
66. Gardiner Garden M and Frommer M. CPG inland in vertebrate genomes.J Mol Biol,1987,196(1):2612-2821.
67. Han HJ ,Yanagisawa A ,Kato Y,et al . Genetic instibity in pancreatic cancer and pooly differentiated type of gastric cancer.Cancer Res,1993,53 (21):50872-50891.
68. Yamashita K,Arimura Y,Kurokawa S ,et al .Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract.Gut,2000,46(6):7902-7941.
69. Gonzalez-Zulueta M,Ruppert JM,Tokino K,et al.Microsatellite instability In bladder cancer.Cancer Res,1993,53(23):56202-56231.
70. Myeroff LL,Parsons R ,Kim SJ ,et al . A transforming growth factorβreceptor type Ⅱgene mutation common in colon and gastric but rare in endome trial cancers with microsatellite instability.Cancer Res ,1995 ,55 (23):55452-55471.
71. Gardiner Garden M and Frommer M. CPG inland in vertebrate genomes.J Mol Biol,1987,196(1):2612-2821.
72. Bea HW,Geiser AG,KimDH ,et al.Characterization of the promoter region of the human transforming growth factor β type Ⅱ receptor gene.J Biol Chem,1995,270(49):294602-294681.
73. Miyazono K. TGF-beta/SMAD signaling and its involvement in tumor progression.BiolPharm Bull,2000,23(10):1125-1130.
74. Derynck R,Feng XH. TGF-β receptor signaling.Biochim Biophys Acta,1997,1333 (1):105-150.
75. Arnaldi G, Freddi S, Mancini T, et al. Transforming growth factor beta1 : implications in adrenocortical tumorigenesis.Endocr Res ,2000,26(4):905-910.
76. Lang F , Klingel K, Wagner CA ,et al.Deranged transcriptional regulation of cell volume sensitive kinase hSGK in diabet icnephropathy. Proc Natl Acad Sci USA,2000,97(14) : 8157-8162.
77. Wakefield LM , Piek E , Bottinger EP. TGF beta signaling in mammary gland development and tumorigenesis.J Mammary Gland Biol Neoplasia,2001,6(1):67-82.
78. Park BJ , Park JI,Byun DS,et al.Mitogenic conversion of transforming growth factor beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer.Cancer Res,2000,60(11):3031-3038.
79. Myatt N,Aristodemou P,Neale MH,et al.Abnormalities of the transforming growth factor-beta pathway in ocular melanoma.J Pathol,2000,192(4):511-518.
80. De Caestecker MP , Piek E , Roberts AB. Role of transforming growth factor-beta signaling in cancer.J Natl Cancer Inst ,2000,92 (17):1388-1402.
81. Inman GJ,Allday MJ.Resistance to TGF beta1 correlates with a reduction of TGF-beta typeⅡreceptor expression in Burkitt′s lymphoma and Epstein-Barr virus-transformedβlymphoblastoid cell lines. J Gen Virol , 2000,81(6):1567-1578.
82. Prunier C, Ferrand N ,Frottier B,et al.Mechanismfor mutational inactivation of the tumor suppressor Smad2.Mol Cell Biol,2001,21 (10):3302-3313.
83. Yanagisawa K, Uchida K,Nagatake M ,et al.Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers.Oncogene,2000,19:2305-2311.
84. Muro Cacho CA, Rosario Ortiz K, Livingston S, et al.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the Lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
85. Gorelik L,Flavel RA.Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells.Nat Med,2001,7(10):1118-1122.
86. Kleef J,Ishiwata T,Maruyama H,et a1.The TGF-beta signaling inhibitor Smad7enhances tumorigenicity in pancreatic cancer.Oncogene,1999,18(39):5363-5372.
87. Murocacho CA,Rosario Ortiz K,Liivngston S,et a1.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
88. Woodford-Richens K,Williamson J,Bevan S,et a1.Mlelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium.Cancer Res, 2000,6O(9):2477-2482.
89. Miyaki M,Iijima T,Konishi M,et a1.Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.Oncogene,2004,18(20):3098-3103.
90. Grady WM,Myeroff LL,Swinler SE,et a1.Mutational inactivation of transforming growth factor β receptor type Ⅱ in microsatellite stable colon cancers.Cancer Res,1999 ,59(2):320-324.
91. Lu SL,Zhang W C,Akiyama Y,et a1.Genomic structure of the transforming growth factor beta typeⅡ receptor gene and its mutations in hereditary nonpolyposis colorectal cancers.Cancer Res,1996,56(20):4595-4598.
92. Perlman R,Schiemaam WP,Brooks MW,et a1.TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation.Nature Cell Biol,2001,3(8):708-714.
93. Larisch S,Yi Y,Lotan R,et a1.A novel mitochondrial septin-like protein,ARTS,mediates apoptosis dependent on its P-loop motif . Nature Cel Biol ,2000,2(12):915-921.
94. Valderrama Carvajal H,Cocolakis E,Lacerte A,et a1.Activin/TGF一βinduce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP.Nature Cel Biol,2002,4(12):963-969.
95. Schuster N,Kriegtstein K.Mechanisms of TGF-β-mediated apoptosis.Cell Tissue Res,2002,307(1):1-14.
96. Goumans ,Valdimarsdottir G,Itoh S,et a1.Balancing the activation state of the endothelium via two distinct TGF-βtype I-receptors.EMBOJ,2002,21(7):1743-1753.
97. Rombouts K,Niki T,Greenwel P,et a1 . Trichostatin A , a histone deacetylase inhibitor,suppresses collagen synthesis and prevents TGF-beta(1)-induced fibrogenesis in skin fibroblasts.Exp Cell Res,2002,278(2):184-197.
98. Blobe GC.Schiemarm .Lodishi-IF.Role of tranforming growth factor in human disease.N Engl J Med,2000,342(18):1350-1358.
99. Dennler S,Prunier C,Ferrand N,et a1.C-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity.J Biol Chem,2000,275(37):28858-28865.
100. Tuxhom JA,McAlhany SJ,Yang F,et a1.Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograh model.Cancer Res,2002,62(21):6021-6025.
1. Assoian RK,Komoriyama A ,Meyers CA ,et al.Transforming growth factor-βin human platelets. J Biol Chem,1983,258(11) :7155-7160.
2. Massague J.The transforming growth factor-βfamily.Ann Rev Cell Biol,1990, 6(2): 591-641.
3. Michael R.TGF-βand cancer.Microbes and infection ,1999,1(4):1327-1347.
4. Massague J.How cells read TGF- β singals.Nature Rev Melecular Cell Biol,2000,1(3):169-177.
5. Souza RF,Lei J,Yin J ,et al.A transforming growth factor betaⅠreceptor type Ⅱmutation in ulcerative colitis associated neophasmas . Gastroenterology, 1997, 112 (1):40-45.
6. Miyazono K, Tendijke P, Heldin CH. TGF-βsignaling by Smad proteins. Adv Immunol, 2000,75(1):115-157.
7. Ewen ME,Siuss HK,Laura L,et al.TGF-βInhibition of CDK4 synthesis is lined to cell cycle arrest.Cell,1993,74(6):1009-1020.
8. Tsukazaki T,Chiang TA ,Davison AF , et al.SARA ,a FYVE domain protein that recruits Smad to the TGF-beta receptor.Cell,1998,95(6):770-791.
9. Rooke HM,Crosier KE.The Smad proteins and TGFβsignalling :uncovering a pathway critical in cancer.Pathology,2001,33(1):73-84.
10. Roberts AB, Sporn MB.Physiological actions and clinical application of transforming growth factor-β.Growth Factors,1993,8(4)∶1-6.
11. Sporn MB, Roberts AB. Major advance in the use of growth factor to enhancewound healing.J Clin Invest,1993,92(12):2565-2578.
12. Beck LS, DeGuzman WP, Lee Y,et al.One system icadminist ration of TGF-β1 reverses age or glucocorticoid impaired wound healing.J Clin Invest,1993,92(6)∶2841-2850.
13. Border WA , Noble NA , Ketteler M.TGF-β:a cytokine mediator of glomerulosclerosis and a target fortherapeutic intervention. Kidney Int,1995,47(49):59-67.
14. Qin LH,Chavin KD,Ding Y,et al.Gene transfer for transplantation. Prolongation of allograft survival with TGF-β1.Ann Surg, 1994,220(6):508-510.
15. Jung S, Schluesencer HJ, Schmidt B,et al. Therapeutic effect of TGF-β1 on actively induced EAN but not adoptive transfer EAN. Immunology, 1994,83(11):545-560.
16. Cartney Mc,Francis NL, Wahl SM. Transforming growth factor-β: a matter of life and death.J Leukoc Biol,1994,55(6)∶401-410.
17. Lowrance JH, O’Sullivan FX, Caver TE,et al. Spontaneous elabo rat ion of transforming growth factor βsuppresses host defense against bacterial infection in autoimmune MRL?1pr mice.J Exp Med, 1994,180(12):1693-1780.
18. Border WA,Rouslahti E.Transforming growth factorβin disease: the dark side of tissue repair.J Clin Invest, 1992,90(1):1-12.
19. Wotton D, Lo RS,Lee S,et al.A Smad transcriptional corepressor.Cell, 1999, 97(1): 29-39.
20. Wahl SM.Transforming growth factorβ:The good the bad and the ugly. J Exp M ed,1994,180(10)∶1587-1600.
21. Rowe PM. Clinical potential for factorβ.Lancet,1994,344(11)∶72-79.
22. McKiel V, Gu Z, Wainberg MA,et al. Inhibition of HIV-1 multiplication by transforming growth factor beta 1 and AZT in H IV-1 infected myeloid cells.J Interf Cytokine Res,1995,15(11):849-869.
23. Sporn MB, Roberts AB, Shull JH,et al. Polypeptide transforming growth factors: isolation from bovine sources and use for wound healing in vivo.Science,1983, 219 (10):1329-1335.
24. Chen X, Weisberg E,Fridmacher V ,et al.Smad 4 and FAST-1 in the assembly of activin-responsive factor.Nature,1997,389(6646):85-89.
25. Liberati NT, Datto MB ,Fredrick J P,et al.Smads bind directly to the Jun family of AP1 transcription factors.Proc Natl Acad Sci USA,1999,96 (9):4844-4849.
26. Gill RG. TGF- β prevents islet allograft rejection. Transplant Proc, 1991, 23(8):747-767.
27. McKiel V, Gu Z, Wainberg MA,et al. Inhibition of HIV-1 multiplication by transforming growth factor beta 1 and AZT in HIV-1 infected myeloid cells.J Interf Cytokine Res,1995,15(8)∶849-855.
28. Qin LH, Chavin KD, Ding Y,et al.Gene transfer for transplantation. Prolongation of allograft survival with TGF-β1.Ann Surg,1994,220(11)∶508-515.
29. Erlebacher A,Derynck R.Increased expression of TGF-beta2 in osteoblasts results in an osteoporosis like phenotype. J Cell Bio l, 1996,132(3)∶195-125.
30. Feng XH,Derynck R.A kinase subdomain of TGF-βtype I receptor determines the TGF-βintracellular signaling specificity.EMBOJ,1997,16(233):3912-3923.
31. Itoh S,Itoh F,Goumans MJ,et al.Signaling of TGF-βfamily members through Smad proteins.Eur J Biochem,2000,267(24):6954-6967.
32. Pasche B. Role of TGF-βin cancer.J Cell Physiol,2001,186(2):153-168.
33. Oft M, Heider KH,Beng H,et al.TGF-βsignalling is necessary for carcinoma cell invasiveness and metastasis.Curr Biol,1998,9(11):1243-1252.
34. Kim IY, Zelner DJ, Lee C, et al. The conventional TGF-βreceptor typeI is not required for TGF-β1 signaling in a human prastate cell line LNCaP. Exp Cell Res, 1998,241 (2):151-160.
35. Goggins M, Shekher M, Turnacioglu K, et al . Genetic alterations of the TGF-βreceptor genes in pancreatic and biliary adenocarcinomars. Cancer Res,1998,58(46): 5329-5332.
36. Chen T,DeVries EGE,Hollema H,et al.Structural alterations of TGF-βreceptor genes in cervical carcinoma.Int J Cancer,1999,82 (1):432-451.
37. Wagner M, Kleeff J, Lopzea ME, et al.Transfection of the type I TGF-β receptor Restores TGF-βreponsiveness in pancreatic cancer.Int J Cancer,1998,78(3):255-260.
38. Horie K, Yamashita H, Mogi A,et al. Lack of TGF-βtypeⅡreceptor expression in human retinoblastoma cells.J Cell Physiol 1998 ,175(5) : 305-313.
39. Grady WM, Myeroff LL, Swinler S, et al.Mutational inactivation of TGF-βreceptor type Ⅱin microsatellite stable colon cancers.Cancer Res,1999,59(4):320-324.
40. Yakicier MC,Irmak MB,Romano A , et al.Smad2 and Smad4 gene mutations hepatocellular carcinoma.Oncogene,1999,18(34):4879-4883.
41. Riggins GJ, Kinzler KW, Vogelstein B, et al. Frequency of Smad gene mutations in human cancers.Cancer Res,1997,57(12):2578-2580.
42. Kleeff J, Ishiwata T, Marnyama H, et al.The TGF-βsignaling inhibitor Smad7 enhances tumorigencity in pancreatic cancer.Oncogene,1999,18 (39):5363-5372.
43. Akiyoshi S, Ishii M,Nemoto N ,et al.Targets of transcriptional regulation by TGF-β:expression profile analysis using oligonucleotide arrays .Jpn J Cancer Res,2001,92(3):257-268.
44. Assoian RK, Komoriyama A ,Meyers CA ,et al . Transforming growth factor βin human platelets.J Biol Chem,1983,258(11):7155-7160.
45. Souza RF,Lei J,Yin J,et al.A transforming growth factor beta Ⅰreceptor typeⅡmutation in ulcerative colitis-associated neophasmas. Gastroenterology, 1997,112(1): 402- 451.
46. Massague J. The transforming growth factor-βfamily.Ann Rev Cell Biol,1990, 6(2): 5912-6411.
47. Michael L,Reiss,K. TGF-βand cancer.Microbes and infection,1999,1(4):13272-13471.
48. Souchelnytskyi S ,Tamaki K, Engstrom U ,et al . Phosphrylation of ser465 and ser467 in the terminus of Smad2 mediates interaction with Smad4 and is required for TGF-βsignaling.J Biol Chem,1997,272 (44):281072-281151.
49. Pietenpol JA,Holt JT ,Stein RW,et al.Transforming growth factorβ1 suppression of c-myc gene transcription:role in inhibition of keratinocyte proliferation. Proc Nat1 Acad Sci U S A,1990 ,87 (10) :37482-37621.
50. Paterson IC,Patel V ,Sand JR ,et al.Effects of transforming growth factor beta-1 on growth regulatory genes in tumor derived human oral keratinocytes.Br J Cancer,1995, 72(4): 9222-9271.
51. Ewen ME ,Siuss HK,Laura L ,et al . TGF-βInhibition of CDK4 synthesis is lined to cell cycle arrest.Cell,1993,74(6):10092-10201.
52. Polyak K. Negative regulation of cell growth by TGF beta.Biochem Biophys Acta,1996, 1242(3):1852-1991.
53. Ko TC,Sheng HM,Reisman D ,et al . Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells.Oncogene,1995,10(1):1712-1841.
54. Shingerland JM, Hengst L,Pan CH ,et al . A novel inhibitor of cyclin cdk activity detected in transforming growth factor beta arrested epithelial cells. Mol Cell Biol,1994,14(6):36832-36941.
55. Hannon GL,Beach D ,et al.p15 INK4B is a potiential effector of TGF-beta induced cell cycle arrest.Nature,1994,371(6494):2572-2611.
56. Datto MB,Li Y,Panus JF,et al.Transforming growth factor β induces the cyclin dependent kinase inhibitor p21 through a p53 independent mechanism. Proc Natl AcadSci U S A,1995,92(12):55452-55491.
57. Tsushima H ,Kawatw S,Tamura S ,et al.High level of transforming growth factorβ1 in patients with colorectal cancer : association with disease progression. Gastroenterology, 1996,110(2):2752-2791.
58. Julie AM,James JK,Vivian M,et al.Invasion and metastasis of a mammary tumor involves TGF-βsignaling.Int J Cancer,2001,91(1):762-821.
59. Roberts H ,Anderson E ,James RD ,et al.Transforming growth factor in patients with colorectal cancer:association with disease progression. Gastroenterology,1996, 110(2): 2752-2791.
60. Wang J ,Sun L ,Myeraff LL ,et al . Demonstration that mutation of the type ⅡTGF-βreceptor error positive colon carcinoma cells.J Biol Chem,1995,270(199): 22044-220491.
61. Laure GA ,Souza RF ,Vellucci VF ,et al .Loss of transforming growth factor beat type Ⅱreceptor gene expression in primary human esophageal cancer.Lab Invest,1996, 75 (2): 2632-2721.
62. Tanaks S ,Mori M,Mafune K,et al.A dominant negative mutation growth factor beta receptor typeⅡgene in microsatellite stable oesophageal carcinoma.Br J Cancer, 2000,82(9):15572-15601.
63. Laure GA ,Antonia TM,Antonia SJ ,et al.Missense mutation of the transforming growth factor βtypeⅡreceptor in human head and neck squamous carcinoma cells.Cancer Res,1995,55(18):39822-39871.
64. Marx J. DNA repair defect tied to mutated TGF-βreceptor gene.Science, 1995, 268 (5215) :12762-12801.
65. Johannsdottir JT,Jonasson TG,Bergthorosson JJ ,et al . The effect of mismatch repair deficiency on tumourigenesis;microsatellite instability affecting genes containing short repeated sequences.Int Oncol ,2000 ,16(1):1332-1391.
66. Gebert J,Sun M,Ridder R ,et al .Molecular profiling of sporadic colorectal tumors by microsatellite analysis.Int J Oncol,2000,16(1) :1692-1791.
67. Han HJ ,Yanagisawa A ,Kato Y,et al . Genetic instibity in pancreatic cancer and pooly differentiated type of gastric cancer.Cancer Res,1993,53 (21):50872-50891.
68. Yamashita K,Arimura Y,Kurokawa S ,et al .Microsatellite instability in patients withmultiple primary cancers of the gastrointestinal tract.Gut,2000,46(6):7902-7941.
69. Gonzalez-Zulueta M,Ruppert JM,Tokino K,et al.Microsatellite instability In bladder cancer.Cancer Res,1993,53(23):56202-56231.
70. Myeroff LL,Parsons R ,Kim SJ ,et al . A transforming growth factorβreceptor type Ⅱgene mutation common in colon and gastric but rare in endome trial cancers with microsatellite instability.Cancer Res ,1995 ,55 (23):55452-55471.
71. Gardiner Garden M and Frommer M. CPG inland in vertebrate genomes.J Mol Biol,1987,196(1):2612-2821.
72. Bea HW,Geiser AG,KimDH ,et al.Characterization of the promoter region of the human transforming growth factor β type Ⅱ receptor gene.J Biol Chem,1995, 270(49): 294602-294681.
73. Miyazono K. TGF-beta/SMAD signaling and its involvement in tumor progression.Biol Pharm Bull,2000,23(10):1125-1130.
74. Derynck R,Feng XH. TGF-β receptor signaling.Biochim Biophys Acta,1997,1333 (1):105-150.
75. Arnaldi G, Freddi S, Mancini T, et al. Transforming growth factor beta1 : implications in adrenocortical tumorigenesis.Endocr Res ,2000,26(4):905-910.
76. Lang F , Klingel K, Wagner CA ,et al.Deranged transcriptional regulation of cell volume sensitive kinase hSGK in diabet icnephropathy. Proc Natl Acad Sci USA,2000, 97(14) : 8157-8162.
77. Wakefield LM , Piek E , Bottinger EP. TGF beta signaling in mammary gland development and tumorigenesis.J Mammary Gland Biol Neoplasia,2001,6(1):67-82.
78. Park BJ , Park JI,Byun DS,et al.Mitogenic conversion of transforming growth factor beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer.Cancer Res,2000,60(11):3031-3038.
79. Myatt N,Aristodemou P,Neale MH,et al.Abnormalities of the transforming growth factor-beta pathway in ocular melanoma.J Pathol,2000,192(4):511-518.
80. De Caestecker MP , Piek E , Roberts AB. Role of transforming growth factor-beta signaling in cancer.J Natl Cancer Inst ,2000,92 (17):1388-1402.
81. Inman GJ,Allday MJ.Resistance to TGF beta1 correlates with a reduction of TGF-beta typeⅡreceptor expression in Burkitt′s lymphoma and Epstein-Barr virus-transformedβlymphoblastoid cell lines. J Gen Virol , 2000,81(6):1567-1578.
82. Prunier C, Ferrand N ,Frottier B,et al.Mechanismfor mutational inactivation of the tumor suppressor Smad2.Mol Cell Biol,2001,21 (10):3302-3313.
83. Yanagisawa K, Uchida K,Nagatake M ,et al.Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers.Oncogene,2000,19:2305-2311.
84. Muro Cacho CA, Rosario Ortiz K, Livingston S, et al.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the Lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
85. Kleeff J,Ishiwata T,Maruyama H,et al.The TGF beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene ,1999 , 18(39):5363-5372.
86. Matsuzaki K, Date M, Furukawa F,et al.Regulatory mechanisms for transforming growth factor beta as an autocrine inhibitor in human hepatocellular carcinoma : implications for roles of smads in its growth.Hepatology,2000,32(2):218-227.
87. Blobe GC ,Schiemann WP , Lodish HF. Role of transforming growth factor in human disease. N Eng J Med,2000,342(18):1350-1358.
88. Olsson N,Piek E,Sundstrom M,et al .Transforming growth factor beta mediated mast cellmigration depends on mitogen activated protein kinase activity. Cell Signal, 2001,13(7):483-490.
89. Furuta K, Misao S, Takahashi K, et al. Gene mutation of transforming growth factor betal type II receptor in hepatocellular carcinoma. Int J Cancer,1999,81(6):851-853.
90. Ueno T , Hashimoto O , Kimura R,et al.Relation of type Ⅱtransforming growth factor beta.receptor to hepatic fibrosis and hepatocellular carcinoma.Int J Oncol,2001, 18(1): 49-55.
91. Kitamura Y, Ninomiya H. Smad expression of hepatic stellate cells in liver cirrhosis in vivo and hepatic stellate cell line in vitro. Pathol Int , 2003,53(1):18-26.
92. Nakao A , Takase M, Nishihara A , et al . Identification of Smad 7 , a TGF-βinducible antaganist of TGF-βsignaling. Nature, 1997,389 (6651):6312-6351.
93. Gagandeep S,OHM, Nisen PD , et al . Overexpression of Mad transcription factor inhibits proliferation of cultured human hepatocellular carcinoma cells along with tumor formation in immunodeficient animals. J Gene Med ,2000,2(2):1172-1271.
94. Evans RA,Tian YC,Steadman R,et al.TGF-betal-mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins. Exp Cell Res,2003,282(2):902-1001.
95. Abour S, Shady M, Baer HU ,Friess H,et al.Transfornling growth factor betas and their signaling receptors in human hepatocellular carcinoma. Am J Surg,1999, 177(3): 209-215.
96. Sacco R,Leuci D,ToHorella C,et al.Transforming growth factor betal and soluble Fas serumlevels in hepatocellular carcinoma. Cytokine,2000,12(6):811-814.
97. Ravitz MJ, Wenner CE. Cyclin-dependent kinase regulation during GI phase and cell cycle regulation by TGFp.Adv Cancer Res,1997,71(3):165-207.
98. Jong HS, Lee HS, Kim TY, et al.Anenuation of transforming growth factor beta induced growth inhibition in human hepatocellular carcinoma cell lines by cyclin DI overexpression.Biochem Biophys Res Commun,2002,29(2): 383-389.
99. Matsuzaki K,Date M,Furukawa F,et al.Ragulatory mechanisms for transforming growth factorp as an autocrine inhibitor in human hepatocellular carcinoma :implications for role of gmads in its growth. Hepatology,2000,32(2):2182-2271.
100. Matsuzaki K, Date M, Furukawa F , et al . Autocrine stimulatory mechanism by tcansforming growth factor beta in human hepatocellular carcinoma.Cancer Res,2000, 60(5): 1394-1402.
101. Yuen MF,Nouis S,Evans LW,et al.Transforming growth factor betal,actvin and follistation in patients with hepatocellular carcinoma and patients with alcoholic cirrhosis. Scand J Gastroenterol,2002,37(2):233-238.
102. Mouri H,Sakaguchi K,Sawayama T,et al.Suppressive effects of transforming growth factor-betal produced by hepatocellular carcinoma cell lines on interferon gamma production by peripheral blood mononuclear cells.Acta Med Okayama, 2002, 56(6):309-315.
103. Taipale J, Saharinem J, Oja JK, et al.Extracellular matrix associated transforming growth factor-β: role in cancer cell growth and invasion. Adv Cancer Res,1998, 75 (1):87-134.
104. Giannelli Q Fransvea E , Marinosci F ,et al . Transforming growth factor betal triggers hepatocellular carcinoma invasiveness via alpha3 betal integrin.Am J Pathol,2002,161(1):1832-1931.
105. Song BC , Chung YH , KimJA , et al .Transforming growth factor β1 as a useful serologic marker of small hepatocellular carcinoma. Cancer,2002,94(1):175-180.
106. Tsail JF , Jeng JE , Chuang LY, et al . Clinical evaluation of urinary transforming growth factor-β1 and serumα-fetoprotein as tumour markers of hepatocellular carcinoma. Br J Cancer,1997,75(10):1460-1465.
107. Lecras TD, Hardie WD,Deutsh GH, et al.Transient induction of TGF-alpha disrupts lung morphogenesis, causing pulmonary disease in adulthood.Am J Physio Lung Cell Mol Physiol,2004,287(4):718-729.
108. Rothenbergm L,Lafleur B,Levyd E, et al.Randomized phase II trial of the clinical and biological effects of two dose Levels of gefitinib in patients with recurrent colo-rectal adenocarcinoma.J Clin Onco, 2005,23(36):9265-9274.
109. Ciana P, Ghisletti S,Muss P, et al. Estrogen Receptoralpha,a molecular switch converting transforming growth factoral-pha-mediated proliferation into differentiation in neuroblastoma cells.J Bio l Chem,2003,278(34):31731-31744.
110. Leon GH, Fireston EGL, Bjeldanesl F. Cyto static effects of 3, 3’-diindo lylmethane in human endometrial cancer cells result from an estrogen recep tor-mediated increase in transforming growth factor-alpha expression. Carcinogenesis, 2001,22 (11):1809-1817.
111. Kim J H, Rhoh M. A ctivation of the human transforming growth factor alpha (TGF-alpha) gene by the hepatitis B viral X protein (HBx) through A P2- sites. Mol Cell Biochem,2002,231(12):155-161.
112. Muraoka RS,Dumont N,Ritter CA ,et a1.Blockade of TGF-beta inhibits mammary tumor cell viability,migration,and metastases.J Clin Invest,2002,109(12):1551-1559.
113. Comijn J,Berx G,Vermassen P,et a1.The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.Mol Cell,2001,7(6): 1267-1278.
114. Li C,Guo B,Bemabeu C,et a1.Angiogenesis in breast cancer:the role of transforming growth factor beta and CD105. Microsc Res Tech,2001,52(4):437-449.
115. Tuxhom JA,McAlhany SJ,Yang F,et a1.Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograh model.Cancer Res,2002,62(21):6021-6025.
116. Dong Y,TangL,Letterio jj,et a1.The Smad3 proteinisinvolved in TGF-β inhibition of class Ⅱtransactivator and classⅡ MHC expression.J Immunol,2001, 167 (1):311-319.
117. Gorelik L,Flavel RA.Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells.Nat Med,2001,7(10): 1118-1122.
118. Kleef J,Ishiwata T,Maruyama H,et a1.The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer.Oncogene,1999,18(39):5363-5372.
119. Murocacho CA,Rosario Ortiz K,Liivngston S,et a1.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
120. Woodford-Richens K,Williamson J,Bevan S,et a1.Mlelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium.Cancer Res, 2000,6O(9):2477-2482.
121. Miyaki M,Iijima T,Konishi M,et a1.Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.Oncogene,2004,18(20):3098-3103.
122. Grady WM,Myeroff LL,Swinler SE,et a1.Mutational inactivation of transforming growth factor β receptor type Ⅱ in microsatellite stable colon cancers.Cancer Res,1999 ,59(2):320-324.
123. Lu SL,Zhang W C,Akiyama Y,et a1.Genomic structure of the transforming growth factor beta type Ⅱ receptor gene and its mutations in hereditary nonpolyposis colorectal cancers.Cancer Res,1996,56(20):4595-4598.
124. Perlman R,Schiemaam WP,Brooks MW,et a1.TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation.Nature Cell Biol,2001,3(8):708-714.
125. Larisch S,Yi Y,Lotan R,et a1.A novel mitochondrial septin-like protein,ARTS,mediates apoptosis dependent on its P-loop motif.Nature Cel Biol,2000,2(12): 915-921.
126. Valderrama Carvajal H,Cocolakis E,Lacerte A,et a1.Activin/TGF一βinduce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP.Nature Cel Biol,2002,4(12):963-969.
127. Schuster N,Kriegtstein K.Mechanisms of TGF-β-mediated apoptosis.Cell Tissue Res,2002,307(1):1-14.
128. Goumans ,Valdimarsdottir G,Itoh S,et a1.Balancing the activation state of theendothelium via two distinct TGF-βtype I-receptors.EMBOJ,2002,21(7):1743-1753.
129. Rombouts K,Niki T,Greenwel P,et a1 . Trichostatin A , a histone deacetylase inhibitor,suppresses collagen synthesis and prevents TGF-beta(1)-induced fibrogenesis in skin fibroblasts.Exp Cell Res,2002,278(2):184-197.
130. Blobe GC.Schiemarm .Lodishi-IF.Role of tranforming growth factor in human disease.N Engl J Med,2000,342(18):1350-1358.
131. Dennler S,Prunier C,Ferrand N,et a1.C-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity.J Biol Chem,2000,275(37):28858-28865.
2. Yu J, Lee P, Ehtesham M, et al. Intratumoral T cell subset ratios and Fas ligand expression on brain tumor endothelium. J Neurooncol, 2003,64(3):55-61.
3. Kim H, Lee S, Lee J, et al. Mutational analysis of Fas ligand gene in human non-Hodgkin lymphoma. APMIS, 2003,111(10):490-496.
4. Jian-Jun Chen, Yongnian S, Gary J, et al. Regulation of the Pro inflammatory Effects of Fas Ligand (CD95L). SCIENCE, 1998 , 282(10) :1714-1716.
5. Velasco J, Arici A, Zreik T, et al. Macrophage derived growth factors modulate Fas ligand expression in cultured endometrial stromal cells: a role in endometriosis. Mol Hum Reprod,1999,5(8):642-650.
6. Craig D, Crystal B, Corneliu N, et al. Activation of a caspase-dependent oxidative damage response mediates TGF β 1 apoptosis in rat hepatocytes. Experimental and Molecular Pathology,2003,74(4):256–261.
7. Yuan Z, Barbara A, Elke B,et al. TGF-b1 inhibits caspase-3 activation and neuronal apoptosis in rat hippocampal cultures. Neurochemistry International,2001,38(3): 227– 235.
8. Barna G, Sebestyen A, Chinopoulos C,et al. TGF β 1 kills lymphoma cells using mitochondrial apoptotic pathway with the help of caspase-8. Hepatology,1999,30(11):1215-1222.
9. Laurent G, Shailaja K, Thomas B, et al. Transforming Growth Factor β 1 Inhibits Fas Ligand Expression and Subsequent Activation-induced Cell Death in T Cells via Downregulation of c-Myc. J. Exp. Med,1999,189(7):231–239.
10. Jung YJ. TGF-β1 inhibits Fas-mediated apoptosis by regulating surface Fas and cFLIPL expression in human leukaemia/lymphoma cells. Int J Mol Med. 2004, 13(1):99-104.
11. Gemma A , Uematsu K, Hagiwara K, et al . Mechanism of resistance to growth inhibition by transforming growth factor2beta 1 ( TGF-beta 1) in primary lung cancer and new molecular targets in therapy. Gan To Kagaku Ryoho, 2000 , 27(10) :1253-1259.
12. Pasche B. Role of TGF-βin cancer. J Cell Physiol , 2001,186(2): 153-168.
13. Barna G, Sebestyen A, Chinopoulos C,et al. TGF-β 1 kills lymphoma cells using mitochondrial apoptotic pathway with the help of caspase-8. Hepatology,1999,30(12):1215-1222.
14. Paul CP, Good PD, Winer I ,et al. Effective expression of small interfering RNA in human cells. Nat Biotechnol, 2002,20(5):505-508.
15. Elbashir SM, Harborth j, Lendeckel W, et al . Duplexes of 21-nucleotide RNAs mediate RNA Interference in cultured mammalian cells. Nature, 2001, 411(11): 494-498.
16. Kapadia SB, Brideau-Andersen A, Chisari FV. Interference of hepatitis C virus RNA replication by short interfering RNAs. Proc Natl Acad Sci U S A. 2003,100 (20): 2014- 2018
17. Castanotto D, Li H, Rossi JJ. Functional siRNA expression from transfected PCR products. RNA,2002,8(15): 1454-1460.
18. Paul CP, Good PD, Winer I ,et al. Effective expression of small interfering RNA in human cells. Nat Biotechnol, 2002,20(5):505-508.
19. McCaffrey AP, Nakai H, Pandey K,et al. Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol, 2003, 21(5):639-644.
20. Angela R, Devin L, Queta B, et al. Rational siRNA design for RNA interference. Nat Biotechnol,2004, 22(10): 326-330.
21. 羊正纲,陈智,徐宁,等.载体法筛选乙型肝炎病毒S基因小干扰RNA靶位体系的建立.中华肝脏病杂志,2004,12(4):515-518.
22. 蹇锐,程小星,安静,等.应用载体介导的RNAi技术抑制Bcl-2的表达.第三军医大学学报,2004,4(5):294-297.
23. J.萨姆布鲁克,E.F.弗里奇,T.曼尼阿蒂斯,等.分子克隆实验指南.第二版.北京:科学技术出版社,1992.63-69
24. Schroter M, Peli J, Hahne M, et al. Fas-dependent tissue turnover is implicated in tumor cell clearance. Oncogene, 2000,19(14): 1794-1800.
25. Blobe GC.Schiemarm .Lodish I-IF.Role of transforming growth factor in human disease.N Engl J Med,2000,342(18):1350-1358.
26. Suzuki H,Yagi K,Kondo M ,et a1.C-skj inhibits the TGF-beta signaling pathway through stabilization of inactive Smad complexes on Smad-binding elements.Oncogene, 2004, 23(29): 5068-5076.
27. Shi Y,Massague J.Mechanisms of TGF-βsignaling from cell membrane to the nucleus.Cell,2003,113(14):685-67O.
28. Liu C,Gaca M D,Swenson ES,et a1.Smads 2 and 3 are differentially activated by transforming growth actor-beta (TGF-beta)in quiescent and activated hepatic stellate cells . Constitutive nuclear localization of Smads in activated cells is TGF-beta-independent.J Biol Chem,2003,278(13):11721-11728.
29. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer : a phase Ⅲ trial-INTACT 1.J Clin Oncol.2004, 22(5):777-784.
30. Nukaya I , Yasumoto M, Iwasaki T, et al. Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer, 1999, 80(1) :92-97.
31. Crowley NJ , Slingluff CL , Darrow TL , et al. Generation of human autologous melanoma specific cytotoxic T cells using HLA-A2-matched allogeneic melanomas. Cancer Res, 1990, 50(4) :492-498.
32. Stevens EJ , Jacknin L , Robbins PF , et al . Generation of tumor-specific CTLs from melanoma patients by using peripheral blood stimulated with allogeneic melanoma tumor cell lines. Fine specificity and MART21 melanoma antigen recognition , J Immunol , 1995 , 154(8) :762-771.
33. 冯明亮,季 芸,陆 琼,等.江浙沪地区汉族人群 HLA单体型研究.遗传学报,2003, 30(6): 584-588.
34. Trojan A, Schultze J, Witzens M., et al. Immunoglobulin framework derived peptides function as cytotoxic T-cell epitopes commonly expressed in B-cell malignancies. Nat Med, 2000, 6(4):667–672.
35. Maleno I , Cabrera T, Salinero J , et al . Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas : high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunol Immunother,2002,51(4) : 389-396.
36. Rimmelzwaan G.F, Boon A.C, Geelhoed-Mieras M.M, et al. Human airway epithelial cells present antigen to influenza virus-specific CD8+ CTL inefficiently after incubation with viral protein together with ISCOMATRIX. Vaccine, 2004,22 (6): 2769–2775.
37. Hanagiri T, Yoshino I, Takenoyama M, et al. Effects of interleukin-12 on the induction of cytotoxic T lymphocytes from the regional lymph node lymphocytes of patients with lung adenocarcinoma. Jpn J Cancer Res, 1998,89(2):192-198.
38. Peltenburg LT, Dee R,Schrier PI. Down regulation of HLA class I expression by c-myc in human melanoma is independent of enhancer A. Nucleic Acids Research, 1993, 21(5): 1179-1185.
39. Minzhen X , Qiu G , Jing Z , et a1 . Genetic modulation of tumor antigen presentation.Trends in Blotethnology, 2000, 18(4):167-173.
40. Rosenberg S.Progress in human tumor immunology and immunotherapy.Nature, 2001,41l(4):380-385.
41. Nukaya I , Yasumoto M, Iwasaki T, et al. Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer, 1999 , 80(1) :92-97.
42. Cedrik MB, Ralf G.M, Thomas W, et al. The use of HLA-A*0201-transfected K562 as standard antigen-presenting cells for CD8+T lymphocytes in IFN-γ ELISPOT assays. Journal of Immunological Methods, 2002, 259(1): 95-110.
43. Peltenburg LT, Dee R,Schrier PI. Down regulation of HLA class I expression by c-myc in human melanoma is independent of enhancer A. Nucleic Acids Research, 1993, 21(5): 1179-1185.
44. Maleno I , Cabrera T, Salinero J , et al . Multiple mechanisms generate HLA class I altered phenotypes in laryngeal carcinomas : high frequency of HLA haplotype loss associated with loss of heterozygosity in chromosome region 6p21. Cancer Immunol Immunother , 2002 , 51(4) : 389-396.
45. Nukaya I , Yasumoto M, Iwasaki T, et al. Identification of HLA-A24 epitope peptides of carcinoembryonic antigen which induce tumor-reactive cytotoxic T lymphocyte. Int J Cancer, 1999 , 80(1) :92-97.
46. De Visser K E, Schumacher T N, Kruisbeek Am, et al. CD8+ T cell tolerance and cancer immunotherapy[J]. J Immunother,2003,26(1):1-11.
47. 徐文华,王鈜,孙立荣,等. 重组人粒细胞集落刺激因子对 HL-60 细胞影响的研究. 医学分子生物学杂志,2005,2(3):178-180.
48. De Visser K E, Schumacher T N, Kruisbeek Am, et al. CD8+ T cell tolerance and cancerimmunotherapy. J Immunother,2003,26(1):1-11.
49. Saitoh S , Kurisaka M, Mosi K, et al . Induction of specific cytotoxic T lymphocytes against autologous brain tumor by cross reactive allotumor cell stimulation. Jpn J Cancer Res , 1997 , 88(3) :289-295.
50. Kikuchi T,Akasaki Y,Joki T,et a1.Antitumor activity of interleukir-18 on mouse glioma cells.J Immunother,2000,23(2):184-189.
51. Castelli C, Rivoltini L, Rini F, et al. Heat shock proteins: biological functions and clinical application as personalized vaccines for human cancer. Cancer Immunol Immunother, 2004,53(3):227-23.
52. Wood C M, Goodman P A, Vassilev, A O, et al. CD95(APO-1/CD95)deficiency in infant acute lymphoblastic leukemia: detection of novel soluble Fas splice variants. Eur J Haematol,2003,70(2):156-171.
53. Julie AM,James JK,Vivian M,et al.Invasion and metastasis of a mammary tumor involves TGF-βsignaling.Int J Cancer,2001,91(1):762-821.
54. Roberts H ,Anderson E ,James RD ,et al.Transforming growth factor in patients with colorectal cancer:association with disease progression. Gastroenterology,1996,110(2):2752-2791.
55. Wang J ,Sun L ,Myeraff LL ,et al . Demonstration that mutation of the type ⅡTGF-βreceptor error positive colon carcinoma cells.J Biol Chem,1995,270(199): 22044-220491.
56. Laure GA ,Souza RF ,Vellucci VF ,et al .Loss of transforming growth factor beat type Ⅱ receptor gene expression in primary human esophageal cancer.Lab Invest,1996,75(2):2632-2721.
57. Tanaks S ,Mori M,Mafune K,et al.A dominant negative mutation growth factor beta receptor typeⅡgene in microsatellite stable oesophageal carcinoma.Br J Cancer, 2000,82(9):15572-15601.
58. Laure GA ,Souza RF ,Vellucci VF ,et al .Loss of transforming growth factor beat type Ⅱ receptor gene expression in primary human esophageal cancer.Lab Invest,1996,75(2):2632-2721.
59. Marx J. DNA repair defect tied to mutated TGF- β receptor gene.Science,1995,268(5215) :12762-12801.
60. Johannsdottir JT,Jonasson TG,Bergthorosson JJ ,et al . The effect of mismatch repair deficiency on tumourigenesis;microsatellite instability affecting genes containing short repeated sequences.Int Oncol ,2000 ,16(1):1332-1391.
61. Gebert J,Sun M,Ridder R ,et al .Molecular profiling of sporadic colorectal tumors by microsatellite analysis.Int J Oncol,2000,16(1) :1692-1791.
62. Han HJ ,Yanagisawa A ,Kato Y,et al . Genetic instibity in pancreatic cancer and pooly differentiated type of gastric cancer.Cancer Res,1993,53 (21):50872-50891.
63. Yamashita K,Arimura Y,Kurokawa S ,et al .Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract.Gut,2000,46(6):7902-7941.
64. Gonzalez-Zulueta M,Ruppert JM,Tokino K,et al.Microsatellite instability In bladder cancer.Cancer Res,1993,53(23):56202-56231.
65. Myeroff LL,Parsons R ,Kim SJ ,et al . A transforming growth factorβreceptor type Ⅱgene mutation common in colon and gastric but rare in endome trial cancers with microsatellite instability.Cancer Res ,1995 ,55 (23):55452-55471.
66. Gardiner Garden M and Frommer M. CPG inland in vertebrate genomes.J Mol Biol,1987,196(1):2612-2821.
67. Han HJ ,Yanagisawa A ,Kato Y,et al . Genetic instibity in pancreatic cancer and pooly differentiated type of gastric cancer.Cancer Res,1993,53 (21):50872-50891.
68. Yamashita K,Arimura Y,Kurokawa S ,et al .Microsatellite instability in patients with multiple primary cancers of the gastrointestinal tract.Gut,2000,46(6):7902-7941.
69. Gonzalez-Zulueta M,Ruppert JM,Tokino K,et al.Microsatellite instability In bladder cancer.Cancer Res,1993,53(23):56202-56231.
70. Myeroff LL,Parsons R ,Kim SJ ,et al . A transforming growth factorβreceptor type Ⅱgene mutation common in colon and gastric but rare in endome trial cancers with microsatellite instability.Cancer Res ,1995 ,55 (23):55452-55471.
71. Gardiner Garden M and Frommer M. CPG inland in vertebrate genomes.J Mol Biol,1987,196(1):2612-2821.
72. Bea HW,Geiser AG,KimDH ,et al.Characterization of the promoter region of the human transforming growth factor β type Ⅱ receptor gene.J Biol Chem,1995,270(49):294602-294681.
73. Miyazono K. TGF-beta/SMAD signaling and its involvement in tumor progression.BiolPharm Bull,2000,23(10):1125-1130.
74. Derynck R,Feng XH. TGF-β receptor signaling.Biochim Biophys Acta,1997,1333 (1):105-150.
75. Arnaldi G, Freddi S, Mancini T, et al. Transforming growth factor beta1 : implications in adrenocortical tumorigenesis.Endocr Res ,2000,26(4):905-910.
76. Lang F , Klingel K, Wagner CA ,et al.Deranged transcriptional regulation of cell volume sensitive kinase hSGK in diabet icnephropathy. Proc Natl Acad Sci USA,2000,97(14) : 8157-8162.
77. Wakefield LM , Piek E , Bottinger EP. TGF beta signaling in mammary gland development and tumorigenesis.J Mammary Gland Biol Neoplasia,2001,6(1):67-82.
78. Park BJ , Park JI,Byun DS,et al.Mitogenic conversion of transforming growth factor beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer.Cancer Res,2000,60(11):3031-3038.
79. Myatt N,Aristodemou P,Neale MH,et al.Abnormalities of the transforming growth factor-beta pathway in ocular melanoma.J Pathol,2000,192(4):511-518.
80. De Caestecker MP , Piek E , Roberts AB. Role of transforming growth factor-beta signaling in cancer.J Natl Cancer Inst ,2000,92 (17):1388-1402.
81. Inman GJ,Allday MJ.Resistance to TGF beta1 correlates with a reduction of TGF-beta typeⅡreceptor expression in Burkitt′s lymphoma and Epstein-Barr virus-transformedβlymphoblastoid cell lines. J Gen Virol , 2000,81(6):1567-1578.
82. Prunier C, Ferrand N ,Frottier B,et al.Mechanismfor mutational inactivation of the tumor suppressor Smad2.Mol Cell Biol,2001,21 (10):3302-3313.
83. Yanagisawa K, Uchida K,Nagatake M ,et al.Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers.Oncogene,2000,19:2305-2311.
84. Muro Cacho CA, Rosario Ortiz K, Livingston S, et al.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the Lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
85. Gorelik L,Flavel RA.Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells.Nat Med,2001,7(10):1118-1122.
86. Kleef J,Ishiwata T,Maruyama H,et a1.The TGF-beta signaling inhibitor Smad7enhances tumorigenicity in pancreatic cancer.Oncogene,1999,18(39):5363-5372.
87. Murocacho CA,Rosario Ortiz K,Liivngston S,et a1.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
88. Woodford-Richens K,Williamson J,Bevan S,et a1.Mlelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium.Cancer Res, 2000,6O(9):2477-2482.
89. Miyaki M,Iijima T,Konishi M,et a1.Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.Oncogene,2004,18(20):3098-3103.
90. Grady WM,Myeroff LL,Swinler SE,et a1.Mutational inactivation of transforming growth factor β receptor type Ⅱ in microsatellite stable colon cancers.Cancer Res,1999 ,59(2):320-324.
91. Lu SL,Zhang W C,Akiyama Y,et a1.Genomic structure of the transforming growth factor beta typeⅡ receptor gene and its mutations in hereditary nonpolyposis colorectal cancers.Cancer Res,1996,56(20):4595-4598.
92. Perlman R,Schiemaam WP,Brooks MW,et a1.TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation.Nature Cell Biol,2001,3(8):708-714.
93. Larisch S,Yi Y,Lotan R,et a1.A novel mitochondrial septin-like protein,ARTS,mediates apoptosis dependent on its P-loop motif . Nature Cel Biol ,2000,2(12):915-921.
94. Valderrama Carvajal H,Cocolakis E,Lacerte A,et a1.Activin/TGF一βinduce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP.Nature Cel Biol,2002,4(12):963-969.
95. Schuster N,Kriegtstein K.Mechanisms of TGF-β-mediated apoptosis.Cell Tissue Res,2002,307(1):1-14.
96. Goumans ,Valdimarsdottir G,Itoh S,et a1.Balancing the activation state of the endothelium via two distinct TGF-βtype I-receptors.EMBOJ,2002,21(7):1743-1753.
97. Rombouts K,Niki T,Greenwel P,et a1 . Trichostatin A , a histone deacetylase inhibitor,suppresses collagen synthesis and prevents TGF-beta(1)-induced fibrogenesis in skin fibroblasts.Exp Cell Res,2002,278(2):184-197.
98. Blobe GC.Schiemarm .Lodishi-IF.Role of tranforming growth factor in human disease.N Engl J Med,2000,342(18):1350-1358.
99. Dennler S,Prunier C,Ferrand N,et a1.C-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity.J Biol Chem,2000,275(37):28858-28865.
100. Tuxhom JA,McAlhany SJ,Yang F,et a1.Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograh model.Cancer Res,2002,62(21):6021-6025.
1. Assoian RK,Komoriyama A ,Meyers CA ,et al.Transforming growth factor-βin human platelets. J Biol Chem,1983,258(11) :7155-7160.
2. Massague J.The transforming growth factor-βfamily.Ann Rev Cell Biol,1990, 6(2): 591-641.
3. Michael R.TGF-βand cancer.Microbes and infection ,1999,1(4):1327-1347.
4. Massague J.How cells read TGF- β singals.Nature Rev Melecular Cell Biol,2000,1(3):169-177.
5. Souza RF,Lei J,Yin J ,et al.A transforming growth factor betaⅠreceptor type Ⅱmutation in ulcerative colitis associated neophasmas . Gastroenterology, 1997, 112 (1):40-45.
6. Miyazono K, Tendijke P, Heldin CH. TGF-βsignaling by Smad proteins. Adv Immunol, 2000,75(1):115-157.
7. Ewen ME,Siuss HK,Laura L,et al.TGF-βInhibition of CDK4 synthesis is lined to cell cycle arrest.Cell,1993,74(6):1009-1020.
8. Tsukazaki T,Chiang TA ,Davison AF , et al.SARA ,a FYVE domain protein that recruits Smad to the TGF-beta receptor.Cell,1998,95(6):770-791.
9. Rooke HM,Crosier KE.The Smad proteins and TGFβsignalling :uncovering a pathway critical in cancer.Pathology,2001,33(1):73-84.
10. Roberts AB, Sporn MB.Physiological actions and clinical application of transforming growth factor-β.Growth Factors,1993,8(4)∶1-6.
11. Sporn MB, Roberts AB. Major advance in the use of growth factor to enhancewound healing.J Clin Invest,1993,92(12):2565-2578.
12. Beck LS, DeGuzman WP, Lee Y,et al.One system icadminist ration of TGF-β1 reverses age or glucocorticoid impaired wound healing.J Clin Invest,1993,92(6)∶2841-2850.
13. Border WA , Noble NA , Ketteler M.TGF-β:a cytokine mediator of glomerulosclerosis and a target fortherapeutic intervention. Kidney Int,1995,47(49):59-67.
14. Qin LH,Chavin KD,Ding Y,et al.Gene transfer for transplantation. Prolongation of allograft survival with TGF-β1.Ann Surg, 1994,220(6):508-510.
15. Jung S, Schluesencer HJ, Schmidt B,et al. Therapeutic effect of TGF-β1 on actively induced EAN but not adoptive transfer EAN. Immunology, 1994,83(11):545-560.
16. Cartney Mc,Francis NL, Wahl SM. Transforming growth factor-β: a matter of life and death.J Leukoc Biol,1994,55(6)∶401-410.
17. Lowrance JH, O’Sullivan FX, Caver TE,et al. Spontaneous elabo rat ion of transforming growth factor βsuppresses host defense against bacterial infection in autoimmune MRL?1pr mice.J Exp Med, 1994,180(12):1693-1780.
18. Border WA,Rouslahti E.Transforming growth factorβin disease: the dark side of tissue repair.J Clin Invest, 1992,90(1):1-12.
19. Wotton D, Lo RS,Lee S,et al.A Smad transcriptional corepressor.Cell, 1999, 97(1): 29-39.
20. Wahl SM.Transforming growth factorβ:The good the bad and the ugly. J Exp M ed,1994,180(10)∶1587-1600.
21. Rowe PM. Clinical potential for factorβ.Lancet,1994,344(11)∶72-79.
22. McKiel V, Gu Z, Wainberg MA,et al. Inhibition of HIV-1 multiplication by transforming growth factor beta 1 and AZT in H IV-1 infected myeloid cells.J Interf Cytokine Res,1995,15(11):849-869.
23. Sporn MB, Roberts AB, Shull JH,et al. Polypeptide transforming growth factors: isolation from bovine sources and use for wound healing in vivo.Science,1983, 219 (10):1329-1335.
24. Chen X, Weisberg E,Fridmacher V ,et al.Smad 4 and FAST-1 in the assembly of activin-responsive factor.Nature,1997,389(6646):85-89.
25. Liberati NT, Datto MB ,Fredrick J P,et al.Smads bind directly to the Jun family of AP1 transcription factors.Proc Natl Acad Sci USA,1999,96 (9):4844-4849.
26. Gill RG. TGF- β prevents islet allograft rejection. Transplant Proc, 1991, 23(8):747-767.
27. McKiel V, Gu Z, Wainberg MA,et al. Inhibition of HIV-1 multiplication by transforming growth factor beta 1 and AZT in HIV-1 infected myeloid cells.J Interf Cytokine Res,1995,15(8)∶849-855.
28. Qin LH, Chavin KD, Ding Y,et al.Gene transfer for transplantation. Prolongation of allograft survival with TGF-β1.Ann Surg,1994,220(11)∶508-515.
29. Erlebacher A,Derynck R.Increased expression of TGF-beta2 in osteoblasts results in an osteoporosis like phenotype. J Cell Bio l, 1996,132(3)∶195-125.
30. Feng XH,Derynck R.A kinase subdomain of TGF-βtype I receptor determines the TGF-βintracellular signaling specificity.EMBOJ,1997,16(233):3912-3923.
31. Itoh S,Itoh F,Goumans MJ,et al.Signaling of TGF-βfamily members through Smad proteins.Eur J Biochem,2000,267(24):6954-6967.
32. Pasche B. Role of TGF-βin cancer.J Cell Physiol,2001,186(2):153-168.
33. Oft M, Heider KH,Beng H,et al.TGF-βsignalling is necessary for carcinoma cell invasiveness and metastasis.Curr Biol,1998,9(11):1243-1252.
34. Kim IY, Zelner DJ, Lee C, et al. The conventional TGF-βreceptor typeI is not required for TGF-β1 signaling in a human prastate cell line LNCaP. Exp Cell Res, 1998,241 (2):151-160.
35. Goggins M, Shekher M, Turnacioglu K, et al . Genetic alterations of the TGF-βreceptor genes in pancreatic and biliary adenocarcinomars. Cancer Res,1998,58(46): 5329-5332.
36. Chen T,DeVries EGE,Hollema H,et al.Structural alterations of TGF-βreceptor genes in cervical carcinoma.Int J Cancer,1999,82 (1):432-451.
37. Wagner M, Kleeff J, Lopzea ME, et al.Transfection of the type I TGF-β receptor Restores TGF-βreponsiveness in pancreatic cancer.Int J Cancer,1998,78(3):255-260.
38. Horie K, Yamashita H, Mogi A,et al. Lack of TGF-βtypeⅡreceptor expression in human retinoblastoma cells.J Cell Physiol 1998 ,175(5) : 305-313.
39. Grady WM, Myeroff LL, Swinler S, et al.Mutational inactivation of TGF-βreceptor type Ⅱin microsatellite stable colon cancers.Cancer Res,1999,59(4):320-324.
40. Yakicier MC,Irmak MB,Romano A , et al.Smad2 and Smad4 gene mutations hepatocellular carcinoma.Oncogene,1999,18(34):4879-4883.
41. Riggins GJ, Kinzler KW, Vogelstein B, et al. Frequency of Smad gene mutations in human cancers.Cancer Res,1997,57(12):2578-2580.
42. Kleeff J, Ishiwata T, Marnyama H, et al.The TGF-βsignaling inhibitor Smad7 enhances tumorigencity in pancreatic cancer.Oncogene,1999,18 (39):5363-5372.
43. Akiyoshi S, Ishii M,Nemoto N ,et al.Targets of transcriptional regulation by TGF-β:expression profile analysis using oligonucleotide arrays .Jpn J Cancer Res,2001,92(3):257-268.
44. Assoian RK, Komoriyama A ,Meyers CA ,et al . Transforming growth factor βin human platelets.J Biol Chem,1983,258(11):7155-7160.
45. Souza RF,Lei J,Yin J,et al.A transforming growth factor beta Ⅰreceptor typeⅡmutation in ulcerative colitis-associated neophasmas. Gastroenterology, 1997,112(1): 402- 451.
46. Massague J. The transforming growth factor-βfamily.Ann Rev Cell Biol,1990, 6(2): 5912-6411.
47. Michael L,Reiss,K. TGF-βand cancer.Microbes and infection,1999,1(4):13272-13471.
48. Souchelnytskyi S ,Tamaki K, Engstrom U ,et al . Phosphrylation of ser465 and ser467 in the terminus of Smad2 mediates interaction with Smad4 and is required for TGF-βsignaling.J Biol Chem,1997,272 (44):281072-281151.
49. Pietenpol JA,Holt JT ,Stein RW,et al.Transforming growth factorβ1 suppression of c-myc gene transcription:role in inhibition of keratinocyte proliferation. Proc Nat1 Acad Sci U S A,1990 ,87 (10) :37482-37621.
50. Paterson IC,Patel V ,Sand JR ,et al.Effects of transforming growth factor beta-1 on growth regulatory genes in tumor derived human oral keratinocytes.Br J Cancer,1995, 72(4): 9222-9271.
51. Ewen ME ,Siuss HK,Laura L ,et al . TGF-βInhibition of CDK4 synthesis is lined to cell cycle arrest.Cell,1993,74(6):10092-10201.
52. Polyak K. Negative regulation of cell growth by TGF beta.Biochem Biophys Acta,1996, 1242(3):1852-1991.
53. Ko TC,Sheng HM,Reisman D ,et al . Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells.Oncogene,1995,10(1):1712-1841.
54. Shingerland JM, Hengst L,Pan CH ,et al . A novel inhibitor of cyclin cdk activity detected in transforming growth factor beta arrested epithelial cells. Mol Cell Biol,1994,14(6):36832-36941.
55. Hannon GL,Beach D ,et al.p15 INK4B is a potiential effector of TGF-beta induced cell cycle arrest.Nature,1994,371(6494):2572-2611.
56. Datto MB,Li Y,Panus JF,et al.Transforming growth factor β induces the cyclin dependent kinase inhibitor p21 through a p53 independent mechanism. Proc Natl AcadSci U S A,1995,92(12):55452-55491.
57. Tsushima H ,Kawatw S,Tamura S ,et al.High level of transforming growth factorβ1 in patients with colorectal cancer : association with disease progression. Gastroenterology, 1996,110(2):2752-2791.
58. Julie AM,James JK,Vivian M,et al.Invasion and metastasis of a mammary tumor involves TGF-βsignaling.Int J Cancer,2001,91(1):762-821.
59. Roberts H ,Anderson E ,James RD ,et al.Transforming growth factor in patients with colorectal cancer:association with disease progression. Gastroenterology,1996, 110(2): 2752-2791.
60. Wang J ,Sun L ,Myeraff LL ,et al . Demonstration that mutation of the type ⅡTGF-βreceptor error positive colon carcinoma cells.J Biol Chem,1995,270(199): 22044-220491.
61. Laure GA ,Souza RF ,Vellucci VF ,et al .Loss of transforming growth factor beat type Ⅱreceptor gene expression in primary human esophageal cancer.Lab Invest,1996, 75 (2): 2632-2721.
62. Tanaks S ,Mori M,Mafune K,et al.A dominant negative mutation growth factor beta receptor typeⅡgene in microsatellite stable oesophageal carcinoma.Br J Cancer, 2000,82(9):15572-15601.
63. Laure GA ,Antonia TM,Antonia SJ ,et al.Missense mutation of the transforming growth factor βtypeⅡreceptor in human head and neck squamous carcinoma cells.Cancer Res,1995,55(18):39822-39871.
64. Marx J. DNA repair defect tied to mutated TGF-βreceptor gene.Science, 1995, 268 (5215) :12762-12801.
65. Johannsdottir JT,Jonasson TG,Bergthorosson JJ ,et al . The effect of mismatch repair deficiency on tumourigenesis;microsatellite instability affecting genes containing short repeated sequences.Int Oncol ,2000 ,16(1):1332-1391.
66. Gebert J,Sun M,Ridder R ,et al .Molecular profiling of sporadic colorectal tumors by microsatellite analysis.Int J Oncol,2000,16(1) :1692-1791.
67. Han HJ ,Yanagisawa A ,Kato Y,et al . Genetic instibity in pancreatic cancer and pooly differentiated type of gastric cancer.Cancer Res,1993,53 (21):50872-50891.
68. Yamashita K,Arimura Y,Kurokawa S ,et al .Microsatellite instability in patients withmultiple primary cancers of the gastrointestinal tract.Gut,2000,46(6):7902-7941.
69. Gonzalez-Zulueta M,Ruppert JM,Tokino K,et al.Microsatellite instability In bladder cancer.Cancer Res,1993,53(23):56202-56231.
70. Myeroff LL,Parsons R ,Kim SJ ,et al . A transforming growth factorβreceptor type Ⅱgene mutation common in colon and gastric but rare in endome trial cancers with microsatellite instability.Cancer Res ,1995 ,55 (23):55452-55471.
71. Gardiner Garden M and Frommer M. CPG inland in vertebrate genomes.J Mol Biol,1987,196(1):2612-2821.
72. Bea HW,Geiser AG,KimDH ,et al.Characterization of the promoter region of the human transforming growth factor β type Ⅱ receptor gene.J Biol Chem,1995, 270(49): 294602-294681.
73. Miyazono K. TGF-beta/SMAD signaling and its involvement in tumor progression.Biol Pharm Bull,2000,23(10):1125-1130.
74. Derynck R,Feng XH. TGF-β receptor signaling.Biochim Biophys Acta,1997,1333 (1):105-150.
75. Arnaldi G, Freddi S, Mancini T, et al. Transforming growth factor beta1 : implications in adrenocortical tumorigenesis.Endocr Res ,2000,26(4):905-910.
76. Lang F , Klingel K, Wagner CA ,et al.Deranged transcriptional regulation of cell volume sensitive kinase hSGK in diabet icnephropathy. Proc Natl Acad Sci USA,2000, 97(14) : 8157-8162.
77. Wakefield LM , Piek E , Bottinger EP. TGF beta signaling in mammary gland development and tumorigenesis.J Mammary Gland Biol Neoplasia,2001,6(1):67-82.
78. Park BJ , Park JI,Byun DS,et al.Mitogenic conversion of transforming growth factor beta1 effect by oncogenic Ha-Ras-induced activation of the mitogen-activated protein kinase signaling pathway in human prostate cancer.Cancer Res,2000,60(11):3031-3038.
79. Myatt N,Aristodemou P,Neale MH,et al.Abnormalities of the transforming growth factor-beta pathway in ocular melanoma.J Pathol,2000,192(4):511-518.
80. De Caestecker MP , Piek E , Roberts AB. Role of transforming growth factor-beta signaling in cancer.J Natl Cancer Inst ,2000,92 (17):1388-1402.
81. Inman GJ,Allday MJ.Resistance to TGF beta1 correlates with a reduction of TGF-beta typeⅡreceptor expression in Burkitt′s lymphoma and Epstein-Barr virus-transformedβlymphoblastoid cell lines. J Gen Virol , 2000,81(6):1567-1578.
82. Prunier C, Ferrand N ,Frottier B,et al.Mechanismfor mutational inactivation of the tumor suppressor Smad2.Mol Cell Biol,2001,21 (10):3302-3313.
83. Yanagisawa K, Uchida K,Nagatake M ,et al.Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers.Oncogene,2000,19:2305-2311.
84. Muro Cacho CA, Rosario Ortiz K, Livingston S, et al.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the Lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
85. Kleeff J,Ishiwata T,Maruyama H,et al.The TGF beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer. Oncogene ,1999 , 18(39):5363-5372.
86. Matsuzaki K, Date M, Furukawa F,et al.Regulatory mechanisms for transforming growth factor beta as an autocrine inhibitor in human hepatocellular carcinoma : implications for roles of smads in its growth.Hepatology,2000,32(2):218-227.
87. Blobe GC ,Schiemann WP , Lodish HF. Role of transforming growth factor in human disease. N Eng J Med,2000,342(18):1350-1358.
88. Olsson N,Piek E,Sundstrom M,et al .Transforming growth factor beta mediated mast cellmigration depends on mitogen activated protein kinase activity. Cell Signal, 2001,13(7):483-490.
89. Furuta K, Misao S, Takahashi K, et al. Gene mutation of transforming growth factor betal type II receptor in hepatocellular carcinoma. Int J Cancer,1999,81(6):851-853.
90. Ueno T , Hashimoto O , Kimura R,et al.Relation of type Ⅱtransforming growth factor beta.receptor to hepatic fibrosis and hepatocellular carcinoma.Int J Oncol,2001, 18(1): 49-55.
91. Kitamura Y, Ninomiya H. Smad expression of hepatic stellate cells in liver cirrhosis in vivo and hepatic stellate cell line in vitro. Pathol Int , 2003,53(1):18-26.
92. Nakao A , Takase M, Nishihara A , et al . Identification of Smad 7 , a TGF-βinducible antaganist of TGF-βsignaling. Nature, 1997,389 (6651):6312-6351.
93. Gagandeep S,OHM, Nisen PD , et al . Overexpression of Mad transcription factor inhibits proliferation of cultured human hepatocellular carcinoma cells along with tumor formation in immunodeficient animals. J Gene Med ,2000,2(2):1172-1271.
94. Evans RA,Tian YC,Steadman R,et al.TGF-betal-mediated fibroblast myofibroblast terminal differentiation the role of Smad proteins. Exp Cell Res,2003,282(2):902-1001.
95. Abour S, Shady M, Baer HU ,Friess H,et al.Transfornling growth factor betas and their signaling receptors in human hepatocellular carcinoma. Am J Surg,1999, 177(3): 209-215.
96. Sacco R,Leuci D,ToHorella C,et al.Transforming growth factor betal and soluble Fas serumlevels in hepatocellular carcinoma. Cytokine,2000,12(6):811-814.
97. Ravitz MJ, Wenner CE. Cyclin-dependent kinase regulation during GI phase and cell cycle regulation by TGFp.Adv Cancer Res,1997,71(3):165-207.
98. Jong HS, Lee HS, Kim TY, et al.Anenuation of transforming growth factor beta induced growth inhibition in human hepatocellular carcinoma cell lines by cyclin DI overexpression.Biochem Biophys Res Commun,2002,29(2): 383-389.
99. Matsuzaki K,Date M,Furukawa F,et al.Ragulatory mechanisms for transforming growth factorp as an autocrine inhibitor in human hepatocellular carcinoma :implications for role of gmads in its growth. Hepatology,2000,32(2):2182-2271.
100. Matsuzaki K, Date M, Furukawa F , et al . Autocrine stimulatory mechanism by tcansforming growth factor beta in human hepatocellular carcinoma.Cancer Res,2000, 60(5): 1394-1402.
101. Yuen MF,Nouis S,Evans LW,et al.Transforming growth factor betal,actvin and follistation in patients with hepatocellular carcinoma and patients with alcoholic cirrhosis. Scand J Gastroenterol,2002,37(2):233-238.
102. Mouri H,Sakaguchi K,Sawayama T,et al.Suppressive effects of transforming growth factor-betal produced by hepatocellular carcinoma cell lines on interferon gamma production by peripheral blood mononuclear cells.Acta Med Okayama, 2002, 56(6):309-315.
103. Taipale J, Saharinem J, Oja JK, et al.Extracellular matrix associated transforming growth factor-β: role in cancer cell growth and invasion. Adv Cancer Res,1998, 75 (1):87-134.
104. Giannelli Q Fransvea E , Marinosci F ,et al . Transforming growth factor betal triggers hepatocellular carcinoma invasiveness via alpha3 betal integrin.Am J Pathol,2002,161(1):1832-1931.
105. Song BC , Chung YH , KimJA , et al .Transforming growth factor β1 as a useful serologic marker of small hepatocellular carcinoma. Cancer,2002,94(1):175-180.
106. Tsail JF , Jeng JE , Chuang LY, et al . Clinical evaluation of urinary transforming growth factor-β1 and serumα-fetoprotein as tumour markers of hepatocellular carcinoma. Br J Cancer,1997,75(10):1460-1465.
107. Lecras TD, Hardie WD,Deutsh GH, et al.Transient induction of TGF-alpha disrupts lung morphogenesis, causing pulmonary disease in adulthood.Am J Physio Lung Cell Mol Physiol,2004,287(4):718-729.
108. Rothenbergm L,Lafleur B,Levyd E, et al.Randomized phase II trial of the clinical and biological effects of two dose Levels of gefitinib in patients with recurrent colo-rectal adenocarcinoma.J Clin Onco, 2005,23(36):9265-9274.
109. Ciana P, Ghisletti S,Muss P, et al. Estrogen Receptoralpha,a molecular switch converting transforming growth factoral-pha-mediated proliferation into differentiation in neuroblastoma cells.J Bio l Chem,2003,278(34):31731-31744.
110. Leon GH, Fireston EGL, Bjeldanesl F. Cyto static effects of 3, 3’-diindo lylmethane in human endometrial cancer cells result from an estrogen recep tor-mediated increase in transforming growth factor-alpha expression. Carcinogenesis, 2001,22 (11):1809-1817.
111. Kim J H, Rhoh M. A ctivation of the human transforming growth factor alpha (TGF-alpha) gene by the hepatitis B viral X protein (HBx) through A P2- sites. Mol Cell Biochem,2002,231(12):155-161.
112. Muraoka RS,Dumont N,Ritter CA ,et a1.Blockade of TGF-beta inhibits mammary tumor cell viability,migration,and metastases.J Clin Invest,2002,109(12):1551-1559.
113. Comijn J,Berx G,Vermassen P,et a1.The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion.Mol Cell,2001,7(6): 1267-1278.
114. Li C,Guo B,Bemabeu C,et a1.Angiogenesis in breast cancer:the role of transforming growth factor beta and CD105. Microsc Res Tech,2001,52(4):437-449.
115. Tuxhom JA,McAlhany SJ,Yang F,et a1.Inhibition of transforming growth factor-beta activity decreases angiogenesis in a human prostate cancer-reactive stroma xenograh model.Cancer Res,2002,62(21):6021-6025.
116. Dong Y,TangL,Letterio jj,et a1.The Smad3 proteinisinvolved in TGF-β inhibition of class Ⅱtransactivator and classⅡ MHC expression.J Immunol,2001, 167 (1):311-319.
117. Gorelik L,Flavel RA.Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells.Nat Med,2001,7(10): 1118-1122.
118. Kleef J,Ishiwata T,Maruyama H,et a1.The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic cancer.Oncogene,1999,18(39):5363-5372.
119. Murocacho CA,Rosario Ortiz K,Liivngston S,et a1.Defective transforming growth factor beta signaling pathway in head and neck squamous cell carcinoma as evidenced by the lack of expression of activated Smad2.Clin Cancer Res,2001,7(6):1618-1626.
120. Woodford-Richens K,Williamson J,Bevan S,et a1.Mlelic loss at SMAD4 in polyps from juvenile polyposis patients and use of fluorescence in situ hybridization to demonstrate clonal origin of the epithelium.Cancer Res, 2000,6O(9):2477-2482.
121. Miyaki M,Iijima T,Konishi M,et a1.Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis.Oncogene,2004,18(20):3098-3103.
122. Grady WM,Myeroff LL,Swinler SE,et a1.Mutational inactivation of transforming growth factor β receptor type Ⅱ in microsatellite stable colon cancers.Cancer Res,1999 ,59(2):320-324.
123. Lu SL,Zhang W C,Akiyama Y,et a1.Genomic structure of the transforming growth factor beta type Ⅱ receptor gene and its mutations in hereditary nonpolyposis colorectal cancers.Cancer Res,1996,56(20):4595-4598.
124. Perlman R,Schiemaam WP,Brooks MW,et a1.TGF-β-induced apoptosis is mediated by the adapter protein Daxx that facilitates JNK activation.Nature Cell Biol,2001,3(8):708-714.
125. Larisch S,Yi Y,Lotan R,et a1.A novel mitochondrial septin-like protein,ARTS,mediates apoptosis dependent on its P-loop motif.Nature Cel Biol,2000,2(12): 915-921.
126. Valderrama Carvajal H,Cocolakis E,Lacerte A,et a1.Activin/TGF一βinduce apoptosis through Smad-dependent expression of the lipid phosphatase SHIP.Nature Cel Biol,2002,4(12):963-969.
127. Schuster N,Kriegtstein K.Mechanisms of TGF-β-mediated apoptosis.Cell Tissue Res,2002,307(1):1-14.
128. Goumans ,Valdimarsdottir G,Itoh S,et a1.Balancing the activation state of theendothelium via two distinct TGF-βtype I-receptors.EMBOJ,2002,21(7):1743-1753.
129. Rombouts K,Niki T,Greenwel P,et a1 . Trichostatin A , a histone deacetylase inhibitor,suppresses collagen synthesis and prevents TGF-beta(1)-induced fibrogenesis in skin fibroblasts.Exp Cell Res,2002,278(2):184-197.
130. Blobe GC.Schiemarm .Lodishi-IF.Role of tranforming growth factor in human disease.N Engl J Med,2000,342(18):1350-1358.
131. Dennler S,Prunier C,Ferrand N,et a1.C-Jun inhibits transforming growth factor beta-mediated transcription by repressing Smad3 transcriptional activity.J Biol Chem,2000,275(37):28858-28865.