Dokument

Zusammenfassung:
Das duktale Pankreasadenokarzinom gehört mit einer 5-Jahres-Überlebensrate von <3% und mittlerer Überlebenszeit von ca. 6 Monaten nach Diagnosestellung zu den tödlichsten Tumor-erkrankungen weltweit. Die Vielfalt an Risikofaktoren sowie genetische Heterogenität der Pankreasneoplasien als auch die schlechten Prognosen, die ebenfalls mangelnden Therapieansätze und die hohen Mortalitätsraten zeigen auf, dass die grundlegenden Mechanismen dieser Erkrankung noch nicht ausreichend aufgeklärt sind. Beruhend auf früheren Forschungsarbeiten unserer Arbeitsgruppe konnte ein Kollektiv von 79 Kandidatengenen mit einem spezifischen Expressionsmuster im Pankreastumorgewebe identifiziert werden. Um den Zeit- und Kostenaufwand für die Einzelgenanalyse der 79 Kandidaten zu minimieren, wurde die Methode der reversen Transfektion als eine adäquate Option ausgewählt. Die reverse transfection microarrays erlaubten die parallele Untersuchung einer großen Anzahl an Genen, mit der Möglichkeit zur Klärung der physiologischen Genfunktion und weiteren Eigenschaften der Genprodukte. Zusammenfassend ergab sich nach der Validierung eine Auswahl von 11 aus anfänglich 79 Kandidaten zur Einzelgencharakterisierung. Ein selektiertes Kandidatengen des reverse transfection screening ist die im Pankreaskarzinom überexpremierte G-Protein-gekoppelte Kinase-2 (GRK2, a.k.a. ADRBK1). Unsere tiefergehende Einzelgenanalysen zeigten einen proliferativen und zellzyklusmodulierenden Phänotyp dieses Kandidatengens. Ein zweiter systematischer Ansatz zur Identifikation neuer Kandidatengene umfasste das gesamte humane Kinom. Eine der Ambion® Silencer® Select kinom-wide siRNS Bibliothek wurde verwendet, um in vollautomatisiertem Format sowohl in der transformierten Panc1-Zelllinie als auch in nicht-transformierten Hek293-Zellen die Kinasen einzeln herunter zu regulieren und anschließend einen Apoptoseassay durchzuführen. Diese kinomweite Untersuchung identifizierte TTK als eine in transformierten Zellen repressionsabhängig apoptoseinduzierende Kinase. Die anfängliche Überprüfung der Expression in humanem Gewebe bestätigte eine signifikante pankreastumorspezifische Dysregulation der TTK-Expression. Unsere Resultate der Viabilitätsprüfung, die eine signifikante Reduktion lebender Zellen in Abhängigkeit der TTK-Expression in Tumorzelllinien belegen und sowohl via Immunoblotnachweise als auch mittels durchflusszytometrischen Analysen eine Apoptoseinduktion belegen, verdeutlichen eine pro-tumorigene Funktion von TTK. Darüber hinaus konnte ebenfalls ein Einfluss auf die genomische Stabilität in Tumorzellen sowie eine signifikante Reduktion des substratunabhängigen Wachstums von Tumorzellen in Abwesenheit der TTK-Expression nachgewiesen werden.

Bibliographie / References

1. —. " Pathology of genetically engineered mouse models of pancreatic exocrine cancer: consensus report and recommendations. " Cancer Res., Jan. 2006: 66:95-106.
2. Ungerer, M, M Böhm, JS Elce, E Erdmann, und MJ Lohse. " Altered expression of beta- adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. " Circulation, Feb. 1993: 87(2):454-63.
3. Venter, JG, et al. " The sequence of the human genome. " Science, Feb. 2001: 292(5523):1304-1351.
4. Graham, FL, J Smiley, WC Russell, und R Nairn. " Characteristics of a human cell line transformed by DNA from human adenovirus type 5. " J Gen Virol. , Jul. 1977: 36(1):59-74.
5. Le Maréchal, C, et al. " Two novel severe mutations in the pancreatic secretory trypsin inhibition gene (SPINK1) cause familial and/or hereditary pancreatitis. " Hum Mutat., Feb. 2004: 23(2):205.
6. Zhang, F, M Mönkkönen, S Roth, und M Laiho. " TGF-induced G(1) cell cycle arrest requires the activity of the proteasome pathway. " Exp. Cell Res., Dec. 2002: 281(2):190-6.
7. Lefkowitz, RJ, und EJ Whalen. " Beta-arrestins: traffic cops of cell signaling. " Curr Opin Cell Biol, Apr. 2004: 16(2):162-8.
8. Huth, J, et al. " TimeLapseAnalyzer: multi-target analysis for live-cell imaging and time- lapse microscopy. " Comput Methods Programs Biomed. , Nov. 2011: 104(2):227- 34.
9. Hingorani, SR, et al. " Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. " Cancer Cell, Dec. 2003: 4:437-450.
10. Santaguida, S, C Vernieri, F Villa, A Ciliberto, und A Musacchio. " Evidence that Aurora B is implicated in spindle checkpoint signaling independently of errore correlation. " EMBO J, Apr. 2011: 30(8):1508-19.
11. van der Waal, MS, et al. " Msp1 promotes rapid centromere accumulation of Aurora B. " EMBO Rep., Sep. 2012: 13(9):847-54.
12. Saurin, AT, MS van der Waal, RH Medema, SM Lens, und GJ Kops. " Aurora B potentiates Msp1 activation to ensure rapid checkpoint establishment at the onset of mitosis. " at Nat Commun., kein Datum: 2:316.
13. Hotamisligil, G. S. " Molecular mechanisms of insulin resistance and the role of the adipocyte. " Int. J. Obes. Relat. Metab. Disord., 2002: 24 (Suppl 4), 23-27.
14. Takahashi, T, et al. " Identification of frequent impaired of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers. " Oncogene, Jul. 1999: 18(30)4295-300.
15. Leng, M, DW Chan, H Luo, C Zhu, und J Qin. " MSP1-dependent mitotic BLM phosphorylation is important for chromosome stability. " Proc Natl Acad Sci USA, Aug. 2006: 103(31):11485-90.
16. Tipton, AR, et al. " Monopolar Spindle 1 (Msp1) kinase promotes production of closed MAD2 (C-MAD2) and assembly of the Mitotic Checkpoint Complex. " J Biol Chem., Oct. 2013: M113.522375.
17. Wei, JH, et al. " TTK/hMsp1 participates in the regulation of ddamage checkpoint response by phosphorylating CHK2 on threonin 68. " J Biol Chem., Mar. 2005: 280(9):7748- 57.
18. Yamaguchi, K, K Yokohata, H Noshiro, K Chijiiwa, und M Tanaka. " Mucinous cystic neoplasm of the pancreas or intraductal papillary-mucinous tumour of the pancreas. " Eur J Surg., 2000: 166(2):141-8.
19. Kalitsis, P, E Earle, KJ Fowler, und KH Choo Murdoch. " Bub3 gene disruption in mice reveals essential mitotic spindle checkpoint function during early embryogenesis. " Genes Dev., Sep. 2001: 14(18)2277-82.
20. Jemal, A, MM Center, C DeSantis, und EM Ward. " Global patterns of cancer incidence and mortality rates and trends. " Cancer Epidemiol Biomarkers Prev., Aug. 2010: 19(8):1893-907.
21. Hocevar, BA, und PH Howe. " Mechnisms of TGF-beta-induced cell cycle arrest. " Miner Electrolyte Metab., 1998: 24(2-3):131-5.
22. Schmitt, CA, et al. " A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. " Cell, Mar. 2002: 109(3):335-46.
23. Stony, Brook. " Frizzleds: new members of the superfamily of G-protein-coupled receptors. " Front Biosci., May 2004: 9:1048-58.
24. International Agency for research on cancer; WHO; GLOBOCAB. Factsheets. 2008. http://globocan.iarc.fr/factsheet.asp (Zugriff am 2013).
25. Zhang, Jie, Chuanhai Fu, Yong Miao, Zhen Dou, und Xuebiao Yao. " Protein kinase TTK interacts and co-localizes with CENP-E to the kinetochore of human cells. " Sci Bull, 2002: 27:213-9.
26. Kushner, S.R, H.W Boyer, und S Nicosia. " An improved method fpr transformation of Escherichia coli with Co/El derived plasmnid. " Genetic Engineering, 1978: 17-23.
27. Gress, TM, et al. " A pancreatic cancer-specific expression profile. " Oncogene, 1996: 13(8):1819-1830.
28. Heasley, LE. " Autocrine and paracrine signaling through neuropeptide receptors in human cancer. " Oncogene, Mar. 2001: 26:20(13):1563-9.
29. Goodman, O.B, J.G Krupnick, F Santini, V.V Gurevich, R.B Penn, und A.W Gagnon. " Beta- arrestin acts as s clathrin adapter in endocytosis of the ß2-adrenergic receptor. " Nature , 1996: 383:447-450.
30. Hahn, SA, et al. " BRCA 2 germline mutations in familial pancreatic carcinoma. " J Natl Cancer Inst., Feb. 2003: 95(3):214-21.
31. Tan, MH, et al. " Characterization of a new primary human pancreatic tumor line. " Cancer Invest. , 1986: 4(1):15-23.
32. Sliedrecht, T, C Zhang, KM Shokat, und GJ Kops. " Chemical genetic inhibition of Msp1 in stable human cell lines reveal aspects of Msp1 function in mitosis. " Plos One, Apr. 2010: 5(4):e10251.
33. Kunapuli, P, und JL Benovic. " Cloning and expression of GRK5: a member of the G protein- coupled receptor kinase family. " Proc. Natl Acad Sci USA, Jun. 1993: 90(12):5588- 92.
34. Roth, N. S, P. T. Campbell, M. G. Caron, R. J. Lefkowitz, und M. J. Lohse. " Comparativ rates of desensitization of beta-adrenergic receptor kinase and the cyclin AMP- dependent protein kinase. " Proc Natl Acad Sci USA, 1991: 88:6201-4.
35. Xia, G, X Luo, T Habu, J Rizo, T Matsumoto, und H Yu. " Conformation-specific binding of p31(comet) antagonizes the function of Mad2 in the spindle checkpoint. " EMBO J, Aug. 2004: 23(15):3133-43.
36. Sato, N, N Fukushima, RH Hruba, und M Goggins. " CpG island methylation profile of pancreatic intaepithelial neoplasia. " Mod Pathol., Mar. 2008: 21(3):238-44.
37. Lippicott-Schwartz, J, und GH Patterson. " Development and use of fluorscent protein markers in living cells. " Science, 2003: 300:87-91.
38. Weitzel, DH, und DD Vandré. " Differential spindle assembly checkpoint response in human lung adenocarcinoma cells. " Cell Tissue Res., Apr. 2000: 300(1):57-65.
39. Santaguida, S, A Tighe, AM D'Alise, SS Taylor, und A Musacchio. " Dissecting the role of MSP1 in chromosome biorientation and the spindle checkpoint through the small molecule inhibition reversine. " J Cell Biol., Jul. 2010: 190(1):73-87.
40. Schutte, M, et al. " DPC4 gene in various tumor types. " Cancer Res., 1996: 56:2527-2530.
41. Suo, WZ, und L Li. " Dysfunction of G protein-coupled receptors kinase in Alzheimer`s disease. " Scientific World Journal, Aug. 2010: 10:1667-78.
42. Iwamura, T, T Katsuki, und K Ide. " Establishment and characterization of a human pancreatic cancer cell line (SUIT-2) producing cardioembryonic antigen and carbohydrate antigen 19-9. " Jpn J Cancer Res., Jan. 1987: 78(1):54-62.
43. Yamamoto, H, et al. " Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. " Cancer Res., Apr. 2001: 61(7):3139-44.
44. Hruba, RH, RE Wlentz, und SE Kern. " Genetics progression in the pancreatic ducts. " Am J Pathol., 2000: 156(6):1821-5.
45. Hanks, SK. " Genomic analisis of the eukaryotic protein kinase superfamiliy: a perspective. " Genome Biol., 2003: 4(5):111.
46. Sears, DA, und MM Udden. " Howeel-Jolly bodies: a brief historical review. " Am J Med Sci., May 2012: 343(5):407-9.
47. Liu, ST, GK Chan, JC Hittle, G Fujii, E Lees, und TJ Yen. " Human Msp1 kinase is required for mitotic arrest induced by the loss of CENP-E from kinetochores. " Mol Biol Cell, Apr. 2003: 14(4):163851.
48. Lehrach, H, et al. " Hybridization fingerpriting in genome mapping and sequencing. " In Genome Analysis Vol 1: Genetic and Physical Mapping., pp39-81. New York: Gold Spring Harbor Laboratory Press., 1990.
49. —. " Inactivation of the p16 (INK4A) tumor supressor gene in pancreatic duct lesions: loss of intranuclear expression. " Cancer Res., 1998: 58:4740-4.
50. Lal, G, et al. " Inherited predisposition to pancreatic adenocarcinoma: role of family history and gemline p16, BRCA1, and BRCA2 mutations. " Cancer Res., Jan. 2000: 60(2):409-416.
51. Tanaka, M, et al. " International consensus guidlines for managment of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of pancreas. " Pancreatology, 2006: 6(1-2)17-32.
52. Young, D, G Waitches, C Birchmeier, O Fasano, und M Wigler. " Isolation and characterization of new cellular oncogene encoding a protein with multiple potential transmembrane domains. " Cell, Jun. 1986: 45(5):711-9.
53. Inglese, J, WJ Koch, MG Caron, und RJ Lefkowitz. " Isoprenylation in regulation of signal transduction by G-protein-coupled receptor kinases. " Nature, Sep. 1992: 359(6391):147-50.
54. Klimstra, D.S, und D.S Longnecker. " K-ras mutation in pancreatic ductal proliferative lesions. " Am. J. Pathol., 1994: 145:1547-1550.
55. Hruban, RH, et al. " K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas usinbg a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. . " Am J Pathol., Aug. 1993: 143:545-554.
56. Zaiuddin, Junaid, und David M Sabatini. " Microarray of cells expressing defined cDNAs. " Nature, May 2001: 411:107-110.
57. Kolonel, L, und L Wilkens. " Migrant studies. Cancer epidemiology and prevention. " Oxford University Press., 2006: 189-201.
58. He, X, MH Jones, und M Winey. " Mph1, a member of the Msp1-like family of dual specificity protein kinases, is required for the spindle checkpoint in S. pombe. " J Cell Sci., Jun. 1998: 111(Pt12):1635-47.
59. Winey, M, L Goetsch, P Baum, und B Byers. " MSP1 and MSP2: novel yeast genes defining distinct steps of spindle pole body duplication. " J Cell Biol., Aug. 1991: 114(4):745- 54.
60. Jelluma, N, et al. " Msp1 phosphorylates Borealin to control Aurora B activity and chromosome aligmenr. " Cell, Jan. 2008: 132(2):23346.
61. Vinge, L. E., E. Oie, Y. Andersson, H. K. Grogaard, G. Andersen, und H. Attramadal. " Myocardial distributionb and regulation of GRK and beta-arrestin isoforms in congrestive heart failure in rats. " Am J Physiol Heart Circ Physiol., 2001: 281:H2490-9.
62. Vilá, MR, J Lloreta, MH Schüssler, G Berrozpe, S Welt, und F.X Real. " New pancreas cancer lines that represent distinct stages of ductal differentiation. " Lab. Invest., Apr. 1995: 72(4):395-404.
63. Köenig, A, et al. " NFAT-induced histone acetylation relay switch promotes c-Myc- dependent growth in pancreatic cancer cells. " Gastroenterology, Mar. 2010: 138(3):1189-99.
64. Korc, M, B Chandrasekar, Y Yamanaka, H Friess, Buchier, M, und HG Beger. " Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increased in the levels of epidermal growth factor and transforming growth factor alpha. . " J. Clin. Invest., 1992: 90:1352-1360.
65. Sihn, C.-R., E.-J. Suh, K.-H. Lee, T.-Y. Kim, und S.-H Kim. " p55CDC/hCD20 mutant induces mitotic catastrophe by inhibiting the Mad-2-dependent spindle checkpoint activity in tumor cells. " Cancer Lett., 2003: 2001:203-210.
66. —. " Pancreatic intraepithelial neoplasia (PanIN): A new nomeclature and classification system for pancreatic duct lesion. " Am J Surg Pathol, May 2001: 25(5):579-86.
67. WHO, S.R Hamilton, und L.A Aaltonen. Pathology and Genetics of Tumours of the Digestive System. France, Lyon: IARC Press, 2000.
68. Schena, M, D Shalon, RW Davis, und PO Brown. " Quantitative monitoring of gene expression patterns with a complementary DNA microarray. " Science, Oct. 1995: 270(5235):467-70.
69. Kohout, TA, und RJ Lefkowitz. " Regulation of G protein-coupled receptor kinase and arrestins during receptor desensitization. " Mol Pharmacol., Jan. 2003: 63(1):9-18.
70. Konrad, A, R Jochmann, E Kuhn, E Naschberger, P Chudasama, und M Stürzl. " Reverse transfection microarray in infections disease research. " Methods Mol. Biol., 2011: 706:107-118.
71. Wang, W, et al. " Structural and mechnistic insights into Msp1 kinase activation. " J Cell Mol Med., Aug. 2009: 13(8b):1679-94.
72. Tesmer, JJ. " Structure and function of regulator of G protein signaling homology domains. " Prog Mol Biol Transl Sci., 2009: 86:75-113.
73. Hewitt, L, et al. " Sustained Msp1 activity is reqiured in mitosis to recruit O-Mad2 to the Mad1-C-Mad2 core complex. . " J Cell Biol. , Jun. 2010: 12:190(1):25-34.
74. Heldin, CH, K Miyazono, und P ten Dijke. " TGF-beta signalling from cell membrane to nucleus through SMAD proteins. " Nature, Dec. 1997: 390(6659):465-71.
75. Weiss, ER, et al. " The cloning of GRK7, a candidate cone opsin kinase, from cone-<and rod-dominant mammalian retinas. " Mol Vis, 1998: 4:27.
76. Sibilia, M, et al. " The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. " Cell, 2000: 102:211-220.
77. Ho, J, E Cocolakis, VM Dumas, BI Posner, SA Laporte, und JJ Lebrun. " The G protein coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction. " EMBO J., Sep. 2005: 24:3247-3258.
78. Stiewe, T. " The p53 family in differentiation and tumorigenesis. " Nat Rev Cancer, Mar. 2007: 7(3):165-8.
79. Klimstra, DS, IR Modlin, D Coppola, RV Lloyd, und S Suster. " The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. " Pancreas. , Aug. 2010: 39(6):707-12.
80. Krupnick, JG, und JL Benovic. " The role of receptor kinases and arrestins in G protein- coupled receptor regulation. " Annu Rev Pharnacol Toxicol., 1998: 38:289-319.
81. Rozenblum, E, et al. " Tumor-suppressive pathways in pancreatic carcinoma. " Cancer Res., May 1997: 57:1731-1734.
82. WHO, IARC, und FT Bosman. WHO classification of tumours of the degistive system. France, Lyon: IARC Press, 2010.
83. World Health Organization. Ten statistical highlights in global public health. World health statistics 2007. Geneva: WHO, 2007.
84. Watanabe, M, A Nobuta, J Tanaka, und M Asaka. " An effect of K-ras gene mutation on epidermal growth factor receptor signal transduction in PANC-1 pancreatic carcinoma cells. " Int. J. Cancer, 1996: 67:264-268.
85. Wagner, M, et al. " Expression of a truncated EGF receptor is associated with inhibition of pancreatic cancer cell growth and enhanced sensitivity to cisplatinum. " Int J Cancer. , Dec. 1996: 11;68(6):782-7.
86. Saeki, A, et al. " Frequent impairment of the spindle assembly checkpoint in hepatocellular carcinoma. " Cancer, Apr. 2002: 94(7):2047-54.
87. Lieber, M, J Mazzetta, W Nelson-Rees, M Kaplan, und G Todaro. " Establishment of a continuous tumor-cell line (panc-1) from a human carcinoma of the exocrine pancreas. " Int J Cancer. , May 1975: 15(5):741-7.
88. Harden, TK. " Agonist-induced desentization of the beta-adrenergic receptor-linked adenylate cyclase. " Pharmacol. Rev., Mar. 1983: 35:5-32.
89. Wang, Y, JY Shyy, und S Chien. " Fluorescence protein, live-cell imaging, and mechanobiology: seeing is believing. " Annu. Rev. Biomed. Eng., 2008: 10:1-38.
90. Lefkowitz, RJ, MJ Stadel, und MG Caron. " Adenylate cyclase-coupled beta-adrenergic receptors: structure and mechanisms of activation and desensitization. " Annu Rev Biochem., 1983: 52:159-86.
91. Hanks, SK, und T Hunter. " Protein kinases 6. The eukaryotic protein kinase superfamily: kinase (catalytic) domain structur and classification. " FASEB J., May 1995: 9(8):576-96.
92. Kong, G, R Penn, und J.L Benovic. " A beta-adrenergic receptor kinase dominant negative mutant attenuates desensitization of the beta 2-adrenergic receptor. " J Biol Chem., 1994: 269:13084-13087.
93. Stoffel, RH, RR Randall, RT Premont, RJ Lefkowitz, und J Inglese. " Palmitoylation of G protein-coupled receptors kinase, GRK6. Lipid modification diversity in the GRK family. " J Biol Chem., 1994: 269(45):27791-4.
94. Wang, XW, et al. " Functional interaction of p53 and BLM DNA helicase in apoptosis. " J Biol Chem. 2001 Aug , Aug. 2001: 276(35):32948-55.
95. Taylor, SS, und F McKeon. " Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage. " Cell, May 1997: 89(5):727-35.
96. Howes, N, et al. " Clinical and genetic characteristics of hereditary pancreatitis in Europe. " Clin Gastroenterol. Hepatol., Mar. 2004: 2(3):252-61.
97. Simpson, J.C., R. Wellenreuther, A. Poustka, R Pepperkok, und Wiemann, S. " Systematic subcellular localization of novel proteins identified by large scale cDNA sequencing. " EMBO Rep., 2000: 1:287-292.
98. Sengupta, S, et al. " BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. " EMBO J, Mar. 2011: 22(5)1210-22.
99. Honda, R, R Körner, und EA Nigg. " Exploring the functional interactions between Aurora B, INCENP, and survivin in mitosis. " Mol Biol Cell, Aug. 2003: 14(8):3325-41.
100. Van Heek, NT, et al. " Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. " Am j Pathol., 2002: 161:1541-1547.
101. Wilentz, RE, et al. " Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas : a new marker of DPC4 inactivation. " Am J Pathol. , Jan. 2000: 156(1):37-43.
102. Hruban, Ralph H., Anirban Maitra, Scott E. Kern, und Michael Goggins. " Precursors to Pancreatic Cancer. " Gastroenterol Clin North Am. , Dec. 2007: 36(4): 831–vi.
103. Huxley, R, A Ansary-Moghaddam, Berrington de González A, F Barzi, und M Woodward. " Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. " Br J Cancer, Jun. 2005: 6;92(11):2076-83.
104. Silverman, D T, et al. " Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. " Br J Cancer. , Aug. 1999: 80(11): 1830– 1837.
105. Koorstra, JB, G Feldmann, N Habbe, und A Maitra. " Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs). " Langenbecks Arch Surg. , Jul. 2008: 393(4):561-70.
106. Santaguida, S, und A Mussachhio. " The life and miracles of kinetochores. " EMBO J, Sep. 2009: 28(17):2511-31.
107. Shih, SC, et al. " The L6 protein TM4SF1 is critical for endothelial cell function and tumor angiogenesis. " Cancer Res., Apr. 2009: 69(8):3272-7.
108. Herzog, F, et al. " Structure of the anaphase-promoting complex/cyclosome interacting with a mitotic checkpoint complex. " Science, Mar. 2009: 13:323(5920):1477-81.
109. Wang, F, NP Ulyanova, MS van der Waal, D Patnaik, SM Lens, und JM Higgins. " A positive feedback loop involving Haspin and Aurora B promotes CPC accumulation at centromeres in mitosis. " Curr Biol., Jun. 2011: 21(12):1061-9.
110. Tipton, AR, M Tipton, T Yen, und ST Liu. " Closed MAD2 (C-MAD2) is selectively incorporated into the mitotic checkpoint complex (MCC). " Cell Cycle, Nov. 2011: 10(21):3740-50.
111. Kahn, B. B, und J. S Flier. " Obesity and insulin resistance. . " J. Clin. Invest., 2000: 106:473- 481.
112. Wei, Z, R Hurtt, M Ciccarelli, WJ Koch, und C Doria. " Growth inhibition of human hepatocellular carcinoma cells by overexpression of G-protein-coupled receptor kinase 2. " J Cell Physiol., Jun. 2012: 227(6):2371-7.
113. Whelan, AJ, D Bartsch, und PJ Goodfellow. " Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. " N Engl J Med., Oct. 1995: 333(15):975-7.
114. Hisatomi, O, S Matsuda, T Satoh, S Kotaka, Y Imanishi, und F Tokunaga. " A novel subtype of G-protein-coupled receptor kinase, GRK7, in teleost cone photoreceptors. " FEBS Lett, 1998: 424(3):159-64.
115. Shan, Q, et al. " A cancer/testis antigen microarray to screen autoantibody biomarkers of non-small cell lung cancer. " Cancer Lett., Jan. 2013: 328(1):160-7.
116. Zamboni, G, K Hirabayashi, P Castelli, und AM Lennon. " Precancerous lesions of the pancreas. " Best Pract Res Clin Gastroenterol. , Apr. 2013: 27(2):299-322.

Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten