Analyse biologischer Effekte eines Fibroblasten-Wachstumsfaktor-bindenden Proteins (FGF-BP) in Tumoren über verschiedene Knockdown-Strategien

Fibroblasten Wachstumsfaktoren (FGFs) spielen eine bedeutende Rolle bei der Zellproliferation und -differenzierung. Bei neoplastischem Wachstum fungieren FGFs als potente Mitogene. Einige der tumorrelevanten FGFs binden jedoch mit hoher Affinität an eine oder mehrere Komponenten der extrazellulären...

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Main Author: Schulze, Daniel
Contributors: Kissel, Thomas (Prof. Dr.) (Thesis advisor)
Format: Dissertation
Language:German
Published: Philipps-Universität Marburg 2011
Pharmazeutische Technologie und Biopharmazie
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1. Laemmli, U.K., Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 1970. 227(5259): p. 680-5.


2. Tao, H., et al., Purifying natively folded proteins from inclusion bodies using sarkosyl, Triton X-100, and CHAPS. Biotechniques, 2010. 48(1): p. 61-4.


3. Sledz, C.A., et al., Activation of the interferon system by short-interfering RNAs. Nat Cell Biol, 2003. 5(9): p. 834-9.


4. Kim, D.H., et al., Synthetic dsRNA Dicer substrates enhance RNAi potency and efficacy. Nat Biotech- nol, 2005. 23(2): p. 222-6.


5. Bartel, D.P., MicroRNAs: genomics, biogenesis, mechanism, and function. Cell, 2004. 116(2): p. 281- 97.


6. Kuan, S.F., et al., Characterization of quantitative mucin variants from a human colon cancer cell line. Cancer Res, 1987. 47(21): p. 5715-24.


7. He, Y., et al., Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter. J Natl Cancer Inst, 1998. 90(14): p. 1080-7.


8. Khvorova, A., A. Reynolds, and S.D. Jayasena, Functional siRNAs and miRNAs exhibit strand bias. Cell, 2003. 115(2): p. 209-16.


9. Bertrand, J.R., et al., Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. Biochem Biophys Res Commun, 2002. 296(4): p. 1000-4.


10. Lee, Y., et al., MicroRNA genes are transcribed by RNA polymerase II. Embo J, 2004. 23(20): p. 4051- 60.


11. Lowry, O.H., et al., Protein measurement with the Folin phenol reagent. J Biol Chem, 1951. 193(1): p. 265-75.


12. Cross, D.A., et al., Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature, 1995. 378(6559): p. 785-9.


13. Ng, E.W., et al., Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov, 2006. 5(2): p. 123-32.


14. Brummelkamp, T.R., R. Bernards, and R. Agami, Stable suppression of tumorigenicity by virus- mediated RNA interference. Cancer Cell, 2002. 2(3): p. 243-7.


15. Höbel, S. and A. Aigner, Polyethylenimine (PEI)/siRNA-mediated gene knockdown in vitro and in vivo. Methods Mol Biol, 2010. 623: p. 283-97.


16. Pfaffl, M.W., A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Ac- ids Res, 2001. 29(9): p. e45.


17. Fojo, T. and M. Menefee, Mechanisms of multidrug resistance: the potential role of microtubule- stabilizing agents. Ann Oncol, 2007. 18 Suppl 5: p. v3-8.


18. Roy, H.K., et al., AKT proto-oncogene overexpression is an early event during sporadic colon carcino- genesis. Carcinogenesis, 2002. 23(1): p. 201-5.


19. De Veylder, L., et al., Increased leakiness of the tetracycline-inducible Triple-Op promoter in dividing cells renders it unsuitable for high inducible levels of a dominant negative CDC2aAt gene. J Exp Bot, 2000. 51(351): p. 1647-53.


20. Sykes, J.A., et al., Some properties of a new epithelial cell line of human origin. J Natl Cancer Inst, 1970. 45(1): p. 107-22.


21. Tom, B.H., et al., Human colon adenocarcinoma cells. II. Tumorigenic and organoid expression in vivo and in vitro. J Natl Cancer Inst, 1977. 58(5): p. 1507-12.


22. Holen, T., et al., Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor. Nucleic Acids Res, 2002. 30(8): p. 1757-66.


23. Henriksen, J.R., et al., Comparison of RNAi efficiency mediated by tetracycline-responsive H1 and U6 promoter variants in mammalian cell lines. Nucleic Acids Res, 2007. 35(9): p. e67.


24. Juliano, R., et al., Mechanisms and strategies for effective delivery of antisense and siRNA oligonucleo- tides. Nucleic Acids Res, 2008. 36(12): p. 4158-71.


25. Sakurai, K., et al., A role for human Dicer in pre-RISC loading of siRNAs. Nucleic Acids Res, 2010. 204.


26. Hochheimer, A. and R. Tjian, Diversified transcription initiation complexes expand promoter selectivity and tissue-specific gene expression. Genes Dev, 2003. 17(11): p. 1309-20.


27. Macleod, K.F., et al., p53-dependent and independent expression of p21 during cell growth, differentia- tion, and DNA damage. Genes Dev, 1995. 9(8): p. 935-44.


28. Paddison, P.J., et al., Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev, 2002. 16(8): p. 948-58.


29. Yi, R., et al., Overexpression of exportin 5 enhances RNA interference mediated by short hairpin RNAs and microRNAs. RNA, 2005. 11(2): p. 220-6.


30. Abaza, I. and F. Gebauer, Trading translation with RNA-binding proteins. Rna, 2008. 14(3): p. 404-9.


31. Evan, G.I. and K.H. Vousden, Proliferation, cell cycle and apoptosis in cancer. Nature, 2001. 411(6835): p. 342-8.


32. Schug, J., et al., Promoter features related to tissue specificity as measured by Shannon entropy. Ge- nome Biol, 2005. 6(4): p. R33.


33. Liu, J., et al., Argonaute2 is the catalytic engine of mammalian RNAi. Science, 2004. 305(5689): p. 1437-41.


34. Schwarz, D.S., et al., Asymmetry in the assembly of the RNAi enzyme complex. Cell, 2003. 115(2): p. 199-208.


35. Fedele, M., et al., Human colorectal carcinomas express high levels of high mobility group HMGI(Y) proteins. Cancer Res, 1996. 56(8): p. 1896-901.


36. Bandiera, A., et al., Expression of HMGI(Y) proteins in squamous intraepithelial and invasive lesions of the uterine cervix. Cancer Res, 1998. 58(3): p. 426-31.


37. Crea, F., et al., Epigenetic mechanisms of irinotecan sensitivity in colorectal cancer cell lines. Mol Cancer Ther, 2009. 8(7): p. 1964-73.


38. Harborth, J., et al., Sequence, chemical, and structural variation of small interfering RNAs and short hairpin RNAs and the effect on mammalian gene silencing. Antisense Nucleic Acid Drug Dev, 2003. 13(2): p. 83-105.


39. Martinez, J., et al., Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell, 2002. 110(5): p. 563-74.


40. Elbashir, S.M., et al., Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammal- ian cells. Nature, 2001. 411(6836): p. 494-8.


41. Salmena, L., A. Carracedo, and P.P. Pandolfi, Tenets of PTEN tumor suppression. Cell, 2008. 133(3): p. 403-14.


42. Li, J., N.W. Shworak, and M. Simons, Increased responsiveness of hypoxic endothelial cells to FGF2 is mediated by HIF-1alpha-dependent regulation of enzymes involved in synthesis of heparan sulfate FGF2-binding sites. J Cell Sci, 2002. 115(Pt 9): p. 1951-9.


43. Sambrook, J., Molecular Cloning: A Laboratory Manual. 2006: Cold Spring Harbor Laboratory Press. 245.


44. 11 Curriculum vitae Persönliche Daten Name: Daniel Schulze Geburtstag: 05.04.1979


45. Marshall, N.J., C.J. Goodwin, and S.J. Holt, A critical assessment of the use of microculture tetrazolium assays to measure cell growth and function. Growth Regul, 1995. 5(2): p. 69-84.


46. Pham, J.W., et al., A Dicer-2-dependent 80s complex cleaves targeted mRNAs during RNAi in Droso- phila. Cell, 2004. 117(1): p. 83-94.


47. Moser, A.R., H.C. Pitot, and W.F. Dove, A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science, 1990. 247(4940): p. 322-4.


48. Han, Z., et al., Akt1/protein kinase B alpha is involved in gastric cancer progression and cell prolifera- tion. Dig Dis Sci, 2008. 53(7): p. 1801-10.


49. Datta, S.R., et al., Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death ma- chinery. Cell, 1997. 91(2): p. 231-41.


50. Martinez, J., et al., Analysis of mammalian gene function using small interfering RNAs. Nucleic Acids Res Suppl, 2003(3): p. 333.


51. Livak, K.J. and T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods, 2001. 25(4): p. 402-8.


52. Chen, X., Analysis of the High-Mobility-Group A1 Protein as a Putative Novel Binding Partner for Fibroblast Growth Factor Binding Protein-1. 2006, Philipps-Universität Marburg: Diplom-Arbeit Fachbereich Pharmakologie und Toxikologie.


53. Yaginuma, Y. and H. Westphal, Analysis of the p53 gene in human uterine carcinoma cell lines. Cancer Res, 1991. 51(24): p. 6506-9.


54. Rosini, P., et al., Androgen receptor expression induces FGF2, FGF-binding protein production, and FGF2 release in prostate carcinoma cells: role of FGF2 in growth, survival, and androgen receptor down-modulation. Prostate, 2002. 53(4): p. 310-21.


55. Hashimoto, F., et al., An improved method for separation of low-molecular-weight polypeptides by electrophoresis in sodium dodecyl sulfate-polyacrylamide gel. Anal Biochem, 1983. 129(1): p. 192-9.


56. Gu, J., et al., A novel single tetracycline-regulative adenoviral vector for tumor-specific Bax gene ex- pression and cell killing in vitro and in vivo. Oncogene, 2002. 21(31): p. 4757-64.


57. Gallo, D., et al., Anti-tumour activity of a panel of taxanes toward a cellular model of human cervical cancer. Cancer Chemother Pharmacol, 2000. 45(2): p. 127-32.


58. Birmingham, A., et al., A protocol for designing siRNAs with high functionality and specificity. Nat Protoc, 2007. 2(9): p. 2068-78.


59. Bradford, M.M., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem, 1976. 72: p. 248-54.


60. Malek, A., et al., A sensitive polymerase chain reaction-based method for detection and quantification of metastasis in human xenograft mouse models. Clin Exp Metastasis, 2010. 27(4): p. 261-71. 289. Thornberry, N.A. and Y. Lazebnik, Caspases: enemies within. Science, 1998. 281(5381): p. 1312-6. 290. Hengartner, M.O., The biochemistry of apoptosis. Nature, 2000. 407(6805): p. 770-6.


61. Hamilton, A.J. and D.C. Baulcombe, A species of small antisense RNA in posttranscriptional gene silencing in plants. Science, 1999. 286(5441): p. 950-2.


62. Brummelkamp, T.R., R. Bernards, and R. Agami, A system for stable expression of short interfering RNAs in mammalian cells. Science, 2002. 296(5567): p. 550-3.


63. Liaudet-Coopman, E.D., et al., A tetracycline-responsive promoter system reveals the role of a secreted binding protein for FGFs during the early phase of tumor growth. Biochem Biophys Res Commun, 1996. 229(3): p. 930-7.


64. Wellstein, A., et al., Autocrine growth stimulation by secreted Kaposi fibroblast growth factor but not by endogenous basic fibroblast growth factor. Cell Growth Differ, 1990. 1(2): p. 63-71. 317. Hamburger, A.W., K.A. Lurie, and M.E. Condon, Stimulation of anchorage-independent growth of human tumor cells by interleukin 1. Cancer Res, 1987. 47(21): p. 5612-5. 318. Hamburger, A.W. and C.P. White, Autocrine growth factors for human tumor clonogenic cells. Int J Cell Cloning, 1985. 3(6): p. 399-406.


65. Chen, J.H., X.C. Wang, and J.D. Sato, Bifunctional effects of heparin-binding protein HBp17 on DNA synthesis in cells. Cell Biol Int, 2001. 25(6): p. 567-70.


66. Auslandssemester in Frankreich an der Université de Paris XI (Phytochemie, Biochemie) sowie 4-wöchiges Praktikum im Central-Hospital Claude-Bichat, Paris 2008 Zusatzqualifikation im Pharmarecht am FB Rechtswissenschaften, Philipps-Universität Marburg Beruflicher Werdegang 10/2003 – 10/2004 Pharmaziepraktikum in der Gregorius Apotheke, Aachen und im Klinikum Garmisch-Partenkirchen 2004 Approbation als Apotheker 01/2005 -05/2006


67. Park, J.S. and G.R. Kunkel, Both RNA polymerase III and RNA polymerase II accurately initiate tran- scription from a human U6 promoter in vitro. Biochem Biophys Res Commun, 1995. 214(3): p. 934-40. 278. Editorial, Whither RNAi? Nat Cell Biol, 2003. 5(6): p. 489-90.


68. Bechtel, W. and G. Bauer, Catalase protects tumor cells from apoptosis induction by intercellular ROS signaling. Anticancer Res, 2009. 29(11): p. 4541-57.


69. Aigner, A., Cellular delivery in vivo of siRNA-based therapeutics. Curr Pharm Des, 2008. 14(34): p. 3603-19.


70. Van Cutsem, E., et al., Cetuximab and chemotherapy as initial treatment for metastatic colorectal can- cer. N Engl J Med, 2009. 360(14): p. 1408-17.


71. Mizuguchi, H. and T. Hayakawa, Characteristics of adenovirus-mediated tetracycline-controllable expression system. Biochim Biophys Acta, 2001. 1568(1): p. 21-9.


72. Sonawane, N.D., F.C. Szoka, Jr., and A.S. Verkman, Chloride accumulation and swelling in endosomes enhances DNA transfer by polyamine-DNA polyplexes. J Biol Chem, 2003. 278(45): p. 44826-31. 307.


73. Bachis, A., et al., Chronic antidepressant treatments increase basic fibroblast growth factor and fibro- blast growth factor-binding protein in neurons. Neuropharmacology, 2008. 55(7): p. 1114-20.


74. Meyer-Ficca, M.L., et al., Comparative analysis of inducible expression systems in transient transfec- tion studies. Anal Biochem, 2004. 334(1): p. 9-19.


75. Miyagishi, M., M. Hayashi, and K. Taira, Comparison of the suppressive effects of antisense oligonu- cleotides and siRNAs directed against the same targets in mammalian cells. Antisense Nucleic Acid Drug Dev, 2003. 13(1): p. 1-7.


76. Ohkawa, J. and K. Taira, Control of the functional activity of an antisense RNA by a tetracycline- responsive derivative of the human U6 snRNA promoter. Hum Gene Ther, 2000. 11(4): p. 577-85. 337.


77. Ringvall, M., et al., Defective heparan sulfate biosynthesis and neonatal lethality in mice lacking N- deacetylase/N-sulfotransferase-1. J Biol Chem, 2000. 275(34): p. 25926-30.


78. Carlotti, F., et al., Development of an inducible suicide gene system based on human caspase 8. Cancer Gene Ther, 2005. 12(7): p. 627-39.


79. Boyle, B.J., et al., Differential regulation of a fibroblast growth factor-binding protein by receptor- selective analogs of retinoic acid. Biochem Pharmacol, 2000. 60(11): p. 1677-84.


80. Sherif, Z.A., et al., Downmodulation of bFGF-binding protein expression following restoration of p53 function. Cancer Gene Ther, 2001. 8(10): p. 771-82.


81. Li, W.M. and W.B. Chen, Effect of FGF-BP on angiogenesis in squamous cell carcinoma. Chin Med J (Engl), 2004. 117(4): p. 621-3.


82. Tassi, E., et al., Effects on neurite outgrowth and cell survival of a secreted fibroblast growth factor binding protein upregulated during spinal cord injury. Am J Physiol Regul Integr Comp Physiol, 2007. 293(2): p. R775-83.


83. Donato, N.J., et al., EGF receptor and p21WAF1 expression are reciprocally altered as ME-180 cervi- cal carcinoma cells progress from high to low cisplatin sensitivity. Clin Cancer Res, 2000. 6(1): p. 193- 202.


84. Tassi, E., et al., Enhancement of fibroblast growth factor (FGF) activity by an FGF-binding protein. J Biol Chem, 2001. 276(43): p. 40247-53.


85. Kaighn, M.E., et al., Establishment and characterization of a human prostatic carcinoma cell line (PC- 3). Invest Urol, 1979. 17(1): p. 16-23.


86. Noonberg, S.B., G.K. Scott, and C.C. Benz, Evidence of post-transcriptional regulation of U6 small nuclear RNA. J Biol Chem, 1996. 271(18): p. 10477-81. 340. van de Wetering, M., et al., Specific inhibition of gene expression using a stably integrated, inducible small-interfering-RNA vector. EMBO Rep, 2003. 4(6): p. 609-15.


87. Jung, Y.S., Y. Qian, and X. Chen, Examination of the expanding pathways for the regulation of p21 expression and activity. Cell Signal, 2010. 22(7): p. 1003-12. 371. el-Deiry, W.S., et al., WAF1, a potential mediator of p53 tumor suppression. Cell, 1993. 75(4): p. 817- 25.


88. Lipinski, C.A., et al., Experimental and computational approaches to estimate solubility and permeabil- ity in drug discovery and development settings. Adv Drug Deliv Rev, 2001. 46(1-3): p. 3-26. 298.


89. Chatterjee-Kishore, M. and C.P. Miller, Exploring the sounds of silence: RNAi-mediated gene silencing for target identification and validation. Drug Discov Today, 2005. 10(22): p. 1559-65. 300.


90. Yi, R., et al., Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes Dev, 2003. 17(24): p. 3011-6.


91. Giering, J.C., et al., Expression of shRNA from a tissue-specific pol II promoter is an effective and safe RNAi therapeutic. Mol Ther, 2008. 16(9): p. 1630-6.


92. Newman, D.R., et al., Fibroblast growth factor-binding protein and N-deacetylase/N-sulfotransferase-1 expression in type II cells is modulated by heparin and extracellular matrix. Am J Physiol Lung Cell Mol Physiol, 2007. 293(5): p. L1314-20.


93. Van den Berghe, L., et al., FIF [fibroblast growth factor-2 (FGF-2)-interacting-factor], a nuclear puta- tively antiapoptotic factor, interacts specifically with FGF-2. Mol Endocrinol, 2000. 14(11): p. 1709- 24.


94. Greer, E.L. and A. Brunet, FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene, 2005. 24(50): p. 7410-25.


95. Chatterjee-Kishore, M., From genome to phenome--RNAi library screening and hit characterization using signaling pathway analysis. Curr Opin Drug Discov Devel, 2006. 9(2): p. 231-9.


96. Willis, I.M., RNA polymerase III. Genes, factors and transcriptional specificity. Eur J Biochem, 1993. 212(1): p. 1-11.


97. Kjellen, L., Glucosaminyl N-deacetylase/N-sulphotransferases in heparan sulphate biosynthesis and biology. Biochem Soc Trans, 2003. 31(2): p. 340-2.


98. Pallerla, S.R., et al., Heparan sulfate Ndst1 gene function variably regulates multiple signaling path- ways during mouse development. Dev Dyn, 2007. 236(2): p. 556-63.


99. Cereghino, J.L. and J.M. Cregg, Heterologous protein expression in the methylotrophic yeast Pichia pastoris. FEMS Microbiol Rev, 2000. 24(1): p. 45-66.


100. Macauley-Patrick, S., et al., Heterologous protein production using the Pichia pastoris expression sys- tem. Yeast, 2005. 22(4): p. 249-70.


101. Low, J., et al., High-content imaging analysis of the knockdown effects of validated siRNAs and an- tisense oligonucleotides. J Biomol Screen, 2007. 12(6): p. 775-88.


102. Inoue, H., H. Nojima, and H. Okayama, High efficiency transformation of Escherichia coli with plas- mids. Gene, 1990. 96(1): p. 23-8.


103. Chiappetta, G., et al., High level expression of the HMGI (Y) gene during embryonic development. On- cogene, 1996. 13(11): p. 2439-46.


104. Vedvick, T., et al., High-level secretion of biologically active aprotinin from the yeast Pichia pastoris. J Ind Microbiol, 1991. 7(3): p. 197-201.


105. Chlebova, K., et al., High molecular weight FGF2: the biology of a nuclear growth factor. Cell Mol Life Sci, 2009. 66(2): p. 225-35.


106. Grosschedl, R., K. Giese, and J. Pagel, HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet, 1994. 10(3): p. 94-100.


107. Dahlberg, J.E. and E. Lund, How does III x II make U6? Science, 1991. 254(5037): p. 1462-3. 346.


108. Tom, B.H., et al., Human colonic adenocarcinoma cells. I. Establishment and description of a new line. In Vitro, 1976. 12(3): p. 180-91.


109. Gregory, R.I., et al., Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell, 2005. 123(4): p. 631-40.


110. Calvani, M., et al., Hypoxic induction of an HIF-1alpha-dependent bFGF autocrine loop drives angio- genesis in human endothelial cells. Blood, 2006. 107(7): p. 2705-12.


111. Xie, B., et al., Identification of the fibroblast growth factor (FGF)-interacting domain in a secreted FGF-binding protein by phage display. J Biol Chem, 2006. 281(2): p. 1137-44.


112. Blum, H., H. Beier, and H. Gross, Improved silver staining of plant proteins, RNA and DNA in poly- acrylamide gels. Electrophoresis, 1987. 8(2): p. 93-99.


113. Sioud, M., Induction of inflammatory cytokines and interferon responses by double-stranded and sin- gle-stranded siRNAs is sequence-dependent and requires endosomal localization. J Mol Biol, 2005. 348(5): p. 1079-90.


114. Harris, V.K., et al., Induction of the angiogenic modulator fibroblast growth factor-binding protein by epidermal growth factor is mediated through both MEK/ERK and p38 signal transduction pathways. J Biol Chem, 2000. 275(15): p. 10802-11.


115. Püttmann-Cyrus, S., Induzierte Expression von Toxingenen in Tumorzellen. 2002, Dissertation Fachbereich Biologie; Westfälische Wilhelms-Universität Münster. 323. Baron, U. and H. Bujard, Tet repressor-based system for regulated gene expression in eukaryotic cells: principles and advances. Methods Enzymol, 2000. 327: p. 401-21.


116. Garcia-Calvo, M., et al., Inhibition of human caspases by peptide-based and macromolecular inhibi- tors. J Biol Chem, 1998. 273(49): p. 32608-13.


117. Nguyen, T.K., et al., Inhibition of MEK/ERK1/2 sensitizes lymphoma cells to sorafenib-induced apop- tosis. Leuk Res, 2010. 34(3): p. 379-86.


118. Kim, D.H., et al., Interferon induction by siRNAs and ssRNAs synthesized by phage polymerase. Nat Biotechnol, 2004. 22(3): p. 321-5.


119. Ellington, A.D. and J.W. Szostak, In vitro selection of RNA molecules that bind specific ligands. Na- ture, 1990. 346(6287): p. 818-22.


120. Liaudet-Coopman, E.D., G.J. Berchem, and A. Wellstein, In vivo inhibition of angiogenesis and induc- tion of apoptosis by retinoic acid in squamous cell carcinoma. Clin Cancer Res, 1997. 3(2): p. 179-84.


121. Zhu, N., et al., KLF5 Interacts with p53 in regulating survivin expression in acute lymphoblastic leuke- mia. J Biol Chem, 2006. 281(21): p. 14711-8.


122. Chen, C., et al., KLF5 promotes cell proliferation and tumorigenesis through gene regulation and the TSU-Pr1 human bladder cancer cell line. Int J Cancer, 2006. 118(6): p. 1346-55.


123. Zhao, Y., et al., Kruppel-like factor 5 modulates p53-independent apoptosis through Pim1 survival kinase in cancer cells. Oncogene, 2008. 27(1): p. 1-8.


124. Rao, S., et al., Lovastatin mediated G1 arrest in normal and tumor breast cells is through inhibition of CDK2 activity and redistribution of p21 and p27, independent of p53. Oncogene, 1998. 17(18): p. 2393-402.


125. Long, H.J., 3rd, Management of metastatic cervical cancer: review of the literature. J Clin Oncol, 2007. 25(20): p. 2966-74.


126. Dhanasekaran, D.M.J.G.L., MAPKs: function, regulation, role in cancer and therapeutic targeting MAPKs. Oncogene, 2007. 26: p. 3097-99.


127. Zhang, W. and H.T. Liu, MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res, 2002. 12(1): p. 9-18.


128. Briones, V.R., et al., Mechanism of fibroblast growth factor-binding protein 1 repression by TGF-beta. Biochem Biophys Res Commun, 2006. 345(2): p. 595-601.


129. Arnold, F.H., Metal-affinity separations: a new dimension in protein processing. Biotechnology (N Y), 1991. 9(2): p. 151-6.


130. Schoensiegel, F., et al., MIA (melanoma inhibitory activity) promoter mediated tissue-specific suicide gene therapy of malignant melanoma. Cancer Gene Ther, 2004. 11(6): p. 408-18.


131. Harris, V.K., et al., Mitogen-induced expression of the fibroblast growth factor-binding protein is tran- scriptionally repressed through a non-canonical E-box element. J Biol Chem, 2000. 275(50): p. 39801. 312. Herschman, H.R., Primary response genes induced by growth factors and tumor promoters. Annu Rev Biochem, 1991. 60: p. 281-319.


132. Ameres, S.L., J. Martinez, and R. Schroeder, Molecular basis for target RNA recognition and cleavage by human RISC. Cell, 2007. 130(1): p. 101-12.


133. Gebauer, F. and M.W. Hentze, Molecular mechanisms of translational control. Nat Rev Mol Cell Biol, 2004. 5(10): p. 827-35.


134. Heinzelmann, S. and G. Bauer, Multiple protective functions of catalase against intercellular apoptosis- inducing ROS signaling of human tumor cells. Biol Chem, 2010. 391(6): p. 675-93.


135. Schulze, D., Nanosystems for the delivery of RNAi. Therapeutic Ribonucleic Acids in Brain Tumors, ed. G.R. V. A. Erdmann, J. Barciszewski. 2009: Springer-Verlag Berlin-Heidelberg.


136. Leibovitz, A., et al., New human cancer cell culture lines. I. SW-13, small-cell carcinoma of the adrenal cortex. J Natl Cancer Inst, 1973. 51(2): p. 691-7.


137. Lund, E., et al., Nuclear export of microRNA precursors. Science, 2004. 303(5654): p. 95-8. 357.


138. Reeves, R., Nuclear functions of the HMG proteins. Biochim Biophys Acta, 2010. 1799(1-2): p. 3-14.


139. Studium der Pharmazie, Philipps-Universität Marburg 2001 6-wöchiges Praktikum " Protein-Reinigung " (Aventis-Behring)


140. Harris, V.K., et al., Phorbol ester-induced transcription of a fibroblast growth factor-binding protein is modulated by a complex interplay of positive and negative regulatory promoter elements. J Biol Chem, 1998. 273(30): p. 19130-9.


141. Brus, C., Physicochemical and biological properties of Polyethylenimine based delivery systems for Oligonucleotides and ribozymes, in Dissertation Fachbereich Pharmazie. 2004, Philipps-Universität Marburg. 200.


142. Höbel, S., et al., Polyethylenimine/small interfering RNA-mediated knockdown of vascular endothelial growth factor in vivo exerts anti-tumor effects synergistically with Bevacizumab. J Gene Med, 2010. 12(3): p. 287-300.


143. Coleman, A.B., Positive and negative regulation of cellular sensitivity to anti-cancer drugs by FGF-2. Drug Resist Updat, 2003. 6(2): p. 85-94.


144. Geisbert, T.W., et al., Postexposure protection of non-human primates against a lethal Ebola virus challenge with RNA interference: a proof-of-concept study. Lancet, 2010. 375(9729): p. 1896-905.


145. Clare, J.J., et al., Production of mouse epidermal growth factor in yeast: high-level secretion using Pichia pastoris strains containing multiple gene copies. Gene, 1991. 105(2): p. 205-12. 295.


146. Boonstra, J., Progression through the G1-phase of the on-going cell cycle. J Cell Biochem, 2003. 90(2): p. 244-52.


147. Pai, S.I., et al., Prospects of RNA interference therapy for cancer. Gene Ther, 2006. 13(6): p. 464-77.


148. Simmen, K.A., et al., Proximal sequence element factor binding and species specificity in vertebrate U6 snRNA promoters. J Mol Biol, 1992. 223(4): p. 873-84.


149. Garcia-Calvo, M., et al., Purification and catalytic properties of human caspase family members. Cell Death Differ, 1999. 6(4): p. 362-9.


150. Altucci, L., et al., RAR and RXR modulation in cancer and metabolic disease. Nat Rev Drug Discov, 2007. 6(10): p. 793-810.


151. Reynolds, A., et al., Rational siRNA design for RNA interference. Nat Biotechnol, 2004. 22(3): p. 326- 30.


152. Liaudet-Coopman, E.D. and A. Wellstein, Regulation of gene expression of a binding protein for fibro- blast growth factors by retinoic acid. J Biol Chem, 1996. 271(35): p. 21303-8.


153. Violette, S., et al., Resistance of colon cancer cells to long-term 5-fluorouracil exposure is correlated to the relative level of Bcl-2 and Bcl-X(L) in addition to Bax and p53 status. Int J Cancer, 2002. 98(4): p. 498-504.


154. Suzuki, A., et al., Resistance to Fas-mediated apoptosis: activation of caspase 3 is regulated by cell cycle regulator p21WAF1 and IAP gene family ILP. Oncogene, 1998. 17(8): p. 931-9.


155. Czubayko, F., A.T. Riegel, and A. Wellstein, Ribozyme-targeting elucidates a direct role of pleiotro- phin in tumor growth. J Biol Chem, 1994. 269(33): p. 21358-63.


156. Urban-Klein, B., et al., RNAi-mediated gene-targeting through systemic application of polyethylenimine (PEI)-complexed siRNA in vivo. Gene Ther, 2005. 12(5): p. 461-6.


157. Kurreck, J., RNA interference: from basic research to therapeutic applications. Angew Chem Int Ed Engl, 2009. 48(8): p. 1378-98.


158. Elbashir, S.M., W. Lendeckel, and T. Tuschl, RNA interference is mediated by 21-and 22-nucleotide RNAs. Genes Dev, 2001. 15(2): p. 188-200.


159. Grzelinski, M., et al., RNA interference-mediated gene silencing of pleiotrophin through polyethylen- imine-complexed small interfering RNAs in vivo exerts antitumoral effects in glioblastoma xenografts. Hum Gene Ther, 2006. 17(7): p. 751-66.


160. Medina, M.F. and S. Joshi, RNA-polymerase III-driven expression cassettes in human gene therapy. Curr Opin Mol Ther, 1999. 1(5): p. 580-94.


161. Kunkel, G.R., RNA polymerase III transcription of genes that lack internal control regions. Biochim Biophys Acta, 1991. 1088(1): p. 1-9.


162. Ray, P.E., et al., Role of fibroblast growth factor-binding protein in the pathogenesis of HIV-associated hemolytic uremic syndrome. Am J Physiol Regul Integr Comp Physiol, 2006. 290(1): p. R105-13. 159.


163. Pellegrini, L., Role of heparan sulfate in fibroblast growth factor signalling: a structural view. Curr Opin Struct Biol, 2001. 11(5): p. 629-34.


164. Fusco, A. and M. Fedele, Roles of HMGA proteins in cancer. Nat Rev Cancer, 2007. 7(12): p. 899-910.


165. Dunn, E.A. and S.D. Rader, Secondary structure of U6 small nuclear RNA: implications for spli- ceosome assembly. Biochem Soc Trans, 2010. 38(4): p. 1099-104.


166. Campisi, J., Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell, 2005. 120(4): p. 513-22.


167. Ling, Y.H., N.J. Donato, and R. Perez-Soler, Sensitivity to topoisomerase I inhibitors and cisplatin is associated with epidermal growth factor receptor expression in human cervical squamous carcinoma ME180 sublines. Cancer Chemother Pharmacol, 2001. 47(6): p. 473-80.


168. Harris, V.K., et al., Serum induction of the fibroblast growth factor-binding protein (FGF-BP) is medi- ated through ERK and p38 MAP kinase activation and C/EBP-regulated transcription. Oncogene, 2001. 20(14): p. 1730-8.


169. Yuan, J., et al., shRNA transcribed by RNA Pol II promoter induce RNA interference in mammalian cell. Mol Biol Rep, 2006. 33(1): p. 43-9.


170. Kappel, S., et al., Silencing of mammalian genes by tetracycline-inducible shRNA expression. Nat Pro- toc, 2007. 2(12): p. 3257-69.


171. Haseloff, J. and W.L. Gerlach, Simple RNA enzymes with new and highly specific endoribonuclease activities. 1988. Biotechnology, 1992. 24: p. 264-9.


172. Chomczynski, P. and N. Sacchi, Single-step method of RNA isolation by acid guanidinium thiocyanate- phenol-chloroform extraction. Anal Biochem, 1987. 162(1): p. 156-9.


173. Frangioni, J.V. and B.G. Neel, Solubilization and purification of enzymatically active glutathione S- transferase (pGEX) fusion proteins. Anal Biochem, 1993. 210(1): p. 179-87.


174. Heil, F., et al., Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Sci- ence, 2004. 303(5663): p. 1526-9.


175. Staatsangehörigkeit: Deutsch Geburtsort: Marburg Schule und Studium 1985 -1998


176. Kim, D.H. and J.J. Rossi, Strategies for silencing human disease using RNA interference. Nat Rev Genet, 2007. 8(3): p. 173-184.


177. Suzuki, A., et al., Survivin initiates procaspase 3/p21 complex formation as a result of interaction with Cdk4 to resist Fas-mediated cell death. Oncogene, 2000. 19(10): p. 1346-53.


178. Gluzman, Y., SV40-transformed simian cells support the replication of early SV40 mutants. Cell, 1981. 23(1): p. 175-82.


179. Mitchell, M.T., G.M. Hobson, and P.A. Benfield, TATA box-mediated polymerase III transcription in vitro. J Biol Chem, 1992. 267(3): p. 1995-2005.


180. Berridge, M.V., P.M. Herst, and A.S. Tan, Tetrazolium dyes as tools in cell biology: new insights into their cellular reduction. Biotechnol Annu Rev, 2005. 11: p. 127-52.


181. Hopkins, A.L. and C.R. Groom, The druggable genome. Nat Rev Drug Discov, 2002. 1(9): p. 727-30. 297.


182. Vaughn, J.L., et al., The establishment of two cell lines from the insect Spodoptera frugiperda (Lepidop- tera; Noctuidae). In Vitro, 1977. 13(4): p. 213-7.


183. Zhao, D., et al., The Fbw7 tumor suppressor targets KLF5 for ubiquitin-mediated degradation and suppresses breast cell proliferation. Cancer Res, 2010. 70(11): p. 4728-38.


184. Beer, H.D., et al., The fibroblast growth factor binding protein is a novel interaction partner of FGF-7, FGF-10 and FGF-22 and regulates FGF activity: implications for epithelial repair. Oncogene, 2005. 24(34): p. 5269-77.


185. Goutelle, S., et al., The Hill equation: a review of its capabilities in pharmacological modelling. Fundam Clin Pharmacol, 2008. 22(6): p. 633-48. 282. Hagenbusch, J., Rekombinante Expression und Untersuchungen zur Funktion eines Fibroblasten- Wachstumsfaktor-bindenden Proteins (FGF-BP). 2010, Philipps-Universität Marburg: Dissertation Fachbereich Pharmakologie und Toxikologie.


186. Stoppler, H., et al., The human papillomavirus (HPV) 16 E6 oncoprotein leads to an increase in gene expression of the angiogenic switch molecule FGF-BP in non-immortalized human keratinocytes. On- cogene, 2001. 20(50): p. 7430-6.


187. Bertout, J.A., S.A. Patel, and M.C. Simon, The impact of O2 availability on human cancer. Nat Rev Cancer, 2008. 8(12): p. 967-75.


188. Witzgall, R., et al., The Kruppel-associated box-A (KRAB-A) domain of zinc finger proteins mediates transcriptional repression. Proc Natl Acad Sci U S A, 1994. 91(10): p. 4514-8.


189. Fang, J.Y. and B.C. Richardson, The MAPK signalling pathways and colorectal cancer. Lancet Oncol, 2005. 6(5): p. 322-7.


190. Harper, J.W., et al., The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell, 1993. 75(4): p. 805-16.


191. Beurel, E. and R.S. Jope, The paradoxical pro-and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. Prog Neurobiol, 2006. 79(4): p. 173-89.


192. Mizuguchi, H. and T. Hayakawa, The tet-off system is more effective than the tet-on system for regulat- ing transgene expression in a single adenovirus vector. J Gene Med, 2002. 4(3): p. 240-7. 327.


193. Iyer, V.R., et al., The transcriptional program in the response of human fibroblasts to serum. Science, 1999. 283(5398): p. 83-7.


194. Smrekar, B., et al., Tissue-dependent factors affect gene delivery to tumors in vivo. Gene Ther, 2003. 10(13): p. 1079-88.


195. Rao, M.K. and M.F. Wilkinson, Tissue-specific and cell type-specific RNA interference in vivo. Nat Protoc, 2006. 1(3): p. 1494-501.


196. Gossen, M., et al., Transcriptional activation by tetracyclines in mammalian cells. Science, 1995. 268(5218): p. 1766-9.


197. Davis, M.G. and E.S. Huang, Transfer and expression of plasmids containing human cytomegalovirus immediate-early gene 1 promoter-enhancer sequences in eukaryotic and prokaryotic cells. 1988. 10(1): p. 6-12.


198. Datto, M.B., et al., Transforming growth factor beta induces the cyclin-dependent kinase inhibitor p21 through a p53-independent mechanism. Proc Natl Acad Sci U S A, 1995. 92(12): p. 5545-9. 376.


199. Schagger, H. and G. von Jagow, Tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis for the separation of proteins in the range from 1 to 100 kDa. Anal Biochem, 1987. 166(2): p. 368-79.


200. Liu, X.H., et al., Up-regulation of a fibroblast growth factor binding protein in children with renal diseases. Kidney Int, 2001. 59(5): p. 1717-28.


201. McDonnell, K., et al., Vascular leakage in chick embryos after expression of a secreted binding protein for fibroblast growth factors. Lab Invest, 2005. 85(6): p. 747-55.


202. Amann, E., J. Brosius, and M. Ptashne, Vectors bearing a hybrid trp-lac promoter useful for regulated expression of cloned genes in Escherichia coli. Gene, 1983. 25(2-3): p. 167-78.


203. Hurtado Pico, A., et al., Viral and nonviral factors causing nonspecific replication of tumor-and tissue- specific promoter-dependent oncolytic adenoviruses. Mol Ther, 2005. 11(4): p. 563-77.


204. Grimm, D., et al., Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA path- ways. Nature, 2006. 441(7092): p. 537-41.


205. Jesnowski, R., J. Naehring, and K. Wolf, A rapid and reliable method for PCR-based amplification of chromosomal and mitochondrial DNA from intact yeast cells. Curr Genet, 1995. 27(4): p. 318-9. 254.


206. Mittal, V., Improving the efficiency of RNA interference in mammals. Nat Rev Genet, 2004. 5(5): p. 355-65.


207. Valencia-Sanchez, M.A., et al., Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev, 2006. 20(5): p. 515-24.


208. Bernstein, E., et al., Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature, 2001. 409(6818): p. 363-6.


209. Gietz, R.D., and Schiestl, R. H., Transforming Yeast with DNA. in Methods in Molecular Biology, (Ev- ans, I. H., ed.) Totowa, NJ, 1996: Humana Press 260. Scorer, C.A., et al., Rapid selection using G418 of high copy number transformants of Pichia pastoris for high-level foreign gene expression. Biotechnology (N Y), 1994. 12(2): p. 181-4.


210. Fire, A., et al., Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 1998. 391(6669): p. 806-11.


211. Jung, H., H.A. Seong, and H. Ha, Critical role of cysteine residue 81 of macrophage migration inhibi- tory factor (MIF) in MIF-induced inhibition of p53 activity. J Biol Chem, 2008. 283(29): p. 20383-96.


212. Zhou, H., X.G. Xia, and Z. Xu, An RNA polymerase II construct synthesizes short-hairpin RNA with a quantitative indicator and mediates highly efficient RNAi. Nucleic Acids Res, 2005. 33(6): p. e62. 360.


213. Donze, O. and D. Picard, RNA interference in mammalian cells using siRNAs synthesized with T7 RNA polymerase. Nucleic Acids Res, 2002. 30(10): p. e46.


214. Elbashir, S.M., et al., Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. Embo J, 2001. 20(23): p. 6877-88.


215. Chiu, Y.L. and T.M. Rana, siRNA function in RNAi: a chemical modification analysis. Rna, 2003. 9(9): p. 1034-48.


216. Bohnsack, M.T., K. Czaplinski, and D. Gorlich, Exportin 5 is a RanGTP-dependent dsRNA-binding protein that mediates nuclear export of pre-miRNAs. Rna, 2004. 10(2): p. 185-91.


217. Sohail, M., et al., A simple and cost-effective method for producing small interfering RNAs with high efficacy. Nucleic Acids Res, 2003. 31(7): p. e38.


218. Rychahou, P.G., et al., Targeted molecular therapy of the PI3K pathway: therapeutic significance of PI3K subunit targeting in colorectal carcinoma. Ann Surg, 2006. 243(6): p. 833-42; discussion 843-4.


219. Grunweller, A., et al., Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2'-O-methyl RNA, phosphorothioates and small interfering RNA. Nucleic Acids Res, 2003. 31(12): p. 3185-93.


220. Kappel, S., et al., Tumor inhibition by genomically integrated inducible RNAi-cassettes. Nucleic Acids Res, 2006. 34(16): p. 4527-36.


221. Heron-Milhavet, L., et al., Only Akt1 is required for proliferation, while Akt2 promotes cell cycle exit through p21 binding. Mol Cell Biol, 2006. 26(22): p. 8267-80.


222. Liau, S.S., et al., Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells. Br J Cancer, 2007. 96(6): p. 993-1000.


223. Aguirre-Ghiso, J.A., Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer, 2007. 7(11): p. 834-46.


224. Rychahou, P.G., et al., Akt2 overexpression plays a critical role in the establishment of colorectal can- cer metastasis. Proc Natl Acad Sci U S A, 2008. 105(51): p. 20315-20.


225. Rigou, P., et al., The antiapoptotic protein AAC-11 interacts with and regulates Acinus-mediated DNA fragmentation. Embo J, 2009. 28(11): p. 1576-88.


226. Manning, B.D. and L.C. Cantley, AKT/PKB signaling: navigating downstream. Cell, 2007. 129(7): p. 1261-74.


227. Khan, A.A., et al., Transfection of small RNAs globally perturbs gene regulation by endogenous mi- croRNAs. Nat Biotechnol, 2009. 27(6): p. 549-55.


228. Williams, A.H., et al., MicroRNA-206 delays ALS progression and promotes regeneration of neuro- muscular synapses in mice. Science, 2009. 326(5959): p. 1549-54.


229. Seong, H.A., et al., Reciprocal negative regulation of PDK1 and ASK1 signaling by direct interaction and phosphorylation. J Biol Chem, 2009. 285(4): p. 2397-414.


230. Chendrimada, T.P., et al., TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature, 2005. 436(7051): p. 740-4.


231. Los, M., et al., Switching Akt: from survival signaling to deadly response. Bioessays, 2009. 31(5): p. 492-5.


232. Nogueira, V., et al., Akt determines replicative senescence and oxidative or oncogenic premature se- nescence and sensitizes cells to oxidative apoptosis. Cancer Cell, 2008. 14(6): p. 458-70. 393.


233. Lobo, S.M., S. Ifill, and N. Hernandez, cis-acting elements required for RNA polymerase II and III transcription in the human U2 and U6 snRNA promoters. Nucleic Acids Res, 1990. 18(10): p. 2891-9.


234. Campbell, F.E., Jr. and D.R. Setzer, Transcription termination by RNA polymerase III: uncoupling of polymerase release from termination signal recognition. Mol Cell Biol, 1992. 12(5): p. 2260-72. 277.


235. Greene, L.A. and A.S. Tischler, Establishment of a noradrenergic clonal line of rat adrenal pheochro- mocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A, 1976. 73(7): p. 2424- 8.


236. Simmen, K.A., et al., TFIID is required for in vitro transcription of the human U6 gene by RNA poly- merase III. Embo J, 1991. 10(7): p. 1853-62.


237. Testa, J.R. and A. Bellacosa, AKT plays a central role in tumorigenesis. Proc Natl Acad Sci U S A, 2001. 98(20): p. 10983-5.


238. Kim, A.H., et al., Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1. Mol Cell Biol, 2001. 21(3): p. 893-901.


239. Sanger, F., S. Nicklen, and A.R. Coulson, DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A, 1977. 74(12): p. 5463-7.


240. Grunweller, A. and R.K. Hartmann, RNA interference as a gene-specific approach for molecular medi- cine. Curr Med Chem, 2005. 12(26): p. 3143-61. 301. zu finden unter: http://www.wiley.co.uk/genmed/clinical/.


241. Boshart, M., et al., A very strong enhancer is located upstream of an immediate early gene of human cytomegalovirus. Cell, 1985. 41(2): p. 521-30.