Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/23002
標題: 探討ZNF490變異在肺癌中扮演的角色
Exploring Somatic Alterations of ZNF490 in Lung Cancer
作者: 荊偉杰
Ching, Wei-Chieh
關鍵字: KRAB-ZFPs;全基因組雜合性缺失;loss of heterozygosity;cell migration
出版社: 生命科學系所
引用: 1. Farber, E., The Multistep Nature of Cancer Development. Cancer Res, 1984. 44(10): p. 4217-4223. 2. Fearon, E.R., Human Cancer Syndromes: Clues to the Origin and Nature of Cancer. Science, 1997. 278(5340): p. 1043-1050. 3. Haber, D. and E. Harlow, Tumour-suppressor genes: evolving definitions in the genomic age. Nat Genet, 1997. 16(4): p. 320-322. 4. Tseng, R.-C., et al., Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer. Int. J. Cancer, 2005. 117(2): p. 241-247. 5. Kohno, T. and J. Yokota1, How many tumor suppressor genes are involved in human lung carcinogenesis? Carcinogenesis, 1999. 20(8): p. 1403-1410. 6. Grote HJ, S.V., Böcking A., Molecular cytopathology of lung cancer--prevalence of genetic alterations and their role in the development of molecular biomarkers. Verh Dtsch Ges Pathol., 2003. 87: p. 142-9. 7. JK Field, E.N., MP Stewart, A Swift, T Lilogloul, JM Risk, H Ross, JR Gosney and and R. Donnelly, Fractional allele loss data indicate distinct genetic populations in the development of non-small-cell lung cancer. Br. J. Cancer, 1996. 74(12): p. 1968-74. 8. E J Bellefroid, D.A.P., P J Lecocq, O Revelant, and J A Martial, The evolutionarily conserved Krüppel-associated box domain defines a subfamily of eukaryotic multifingered proteins. Proc Natl Acad Sci U S A., 1991. 88(9): p. 3608-3612. 9. Looman, C., et al., KRAB Zinc Finger Proteins: An Analysis of the Molecular Mechanisms Governing Their Increase in Numbers and Complexity During Evolution. Mol Biol Evol, 2002. 19(12): p. 2118-2130. 10. Urrutia, R., KRAB-containing zinc-finger repressor proteins. Genome Biology, 2003. 4(10): p. 231. 11. Moosmann P, G.O., Thiesen HJ, Hagmann M, Schaffner W., Silencing of RNA polymerases II and III-dependent transcription by the KRAB protein domain of KOX1, a Krüppel-type zinc finger factor. Biol Chem., 1997. 378(7): p. 699-77. 12. Schultz, D.C., et al., SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev., 2002. 16(919-932). 13. Torosyan Y, D.A., Naga S, Mezhevaya K, Glasman M, Norris C, Jiang G, Mueller G, Pollard H, Srivastava M., Distinct effects of annexin A7 and p53 on arachidonate lipoxygenation in prostate cancer cells involve 5-lipoxygenase transcription. Cancer Res., 2006. 66(19). 14. Tian, C., et al., KRAB-type zinc-finger protein Apak specifically regulates p53-dependent apoptosis. Nat. Cell Biol., 2009. 11(5): p. 580-591. 15. Hennemann H, V.L., Geisen C, Eilers M, Möröy T., Identification of a novel Krüppel-associated box domain protein, Krim-1, that interacts with c-Myc and inhibits its oncogenic activity. J Biol Chem., 2003. 278(31). 16. Lin LF, C.C., Li CF, Liao CC, Cheng CP, Cheng TL, Shen MR, Tseng JT, Chang WC, Lee WH, Wang JM., ZBRK1 acts as a metastatic suppressor by directly regulating MMP9 in cervical cancer. Cancer Res. , 2010. 70(1). 17. Huang, X., et al., ZNF569, a novel KRAB-containing zinc finger protein, suppresses MAPK signaling pathway. Biochemical and Biophysical Research Communications, 2006. 346(3): p. 621-628. 18. Chuanxin, H., et al., ZNF23 induces apoptosis in human ovarian cancer cells. Cancer letters, 2008. 266(2): p. 135-143. 19. Cesaro E, D.C.R., Medugno L, Florio F, Grosso M, Lupo A, Izzo P, Costanzo P., The Kruppel-like zinc finger protein ZNF224 recruits the arginine methyltransferase PRMT5 on the transcriptional repressor complex of the aldolase A gene. J Biol Chem., 2009. 284(47): p. 32321-30. 20. Vogelstein, B., D. Lane, and A.J. Levine, Surfing the p53 network. Nature, 2000. 408(6810): p. 307-310. 21. Laptenko, O. and C. Prives, Transcriptional regulation by p53: one protein, many possibilities. Cell Death Differ, 2006. 13(6): p. 951-961. 22. Eferl, R. and E.F. Wagner, AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer, 2003. 3(11): p. 859-868. 23. Dong, P., et al., Elevated expression of p53 gain-of-function mutation R175H in endometrial cancer cells can increase the invasive phenotypes by activation of the EGFR/PI3K/AKT pathway. Molecular Cancer, 2009. 8(1): p. 103. 24. Fukun, G., et al., p19Arf-p53 tumor suppressor pathway regulates cell motility by suppression of phosphoinositide 3-kinase and Rac1 GTPase activities. J Biol Chem, 2003. 278(16): p. 14414-9. 25. Cao, L., et al., ZNF383, a novel KRAB-containing zinc finger protein, suppresses MAPK signaling pathway. Biochemical and Biophysical Research Communications, 2005. 333(4): p. 1050-1059. 26. Li Y, Y.D., Bai Y, Mo X, Huang W, Yuan W, Yin Z, Deng Y, Murashko O, Wang Y, Fan X, Zhu C, Ocorr K, Bodmer R, Wu X., ZNF418, a novel human KRAB/C2H2 zinc finger protein, suppresses MAPK signaling pathway. Molecular and Cellular Biochemistry, 2008. 310(1-2). 27. Luo, K., et al., Activation of transcriptional activities of AP1 and SRE by a novel zinc finger protein ZNF445. Gene, 2006. 367: p. 89-100.
摘要: 
ZNF490 屬於Krupple-associated box-containing zinc finger protein (KRAB-ZFPs) 總科的一份子,在四足類脊椎動物中,有三分之一的鋅手指蛋白被分類為KRAB-ZFPs。KRAB domain調控的基因沉默的機制是由KRAB domain與共同抑制蛋白KAP1(KRAB-associated protein 1) 的相互作用進而改變染色質結構來沉默基因的表現。在我們實驗室先前的研究,我們利用微衛星標記,在48個非小細胞肺癌(NSCLC)病人的樣本中,檢測全基因組雜合性缺失(LOH)的最小缺失區域和地圖(MDRs)。我們發現在同一組的病人的樣本中,ZNF490具有高頻率的LOH和28個突變位置。為了要選出優先測試其功能與可能參與腫瘤發生的突變位置;我挑選出8個發生在KRAB–ZFPs中功能相似的胺基酸之突變位置並且在肺癌細胞測試這些異變在細胞中的功能。當野生型ZNF490被過度表現在三個肺癌細胞株時,野生型ZNF490的作用主要是在抑制細胞遷移而非改變細胞增殖率。然而,一些突變型ZNF490失去抑制細胞遷移的能力。我的研究結果顯示ZNF490可能作用在細胞遷移的行為上。目前為止,我正持續研究在非小細胞肺癌中這些在腫瘤發生過程中突變的ZNF490和評價他們作為治療靶基因的潛能。

ZNF490 is a member of Krupple-associated box-containing zinc finger proteins (KRAB-ZFPs). In tetrapod vertebrate, one-third of zinc finger proteins are KRAB-ZFPs. KRAB-mediated gene silencing requires the interaction of the KRAB domain with the corepressor protein KAP1 (KRAB-associated protein 1) that modified chromatin structure to silence gene expression. Previous study in our laboratory, we used microsatellite markers to detect genome-wide loss of heterozygosity (LOH) and map minimal deletion regions (MDRs) in 48 non small cell lung cancer (NSCLC) patient samples. We found ZNF490 has high frequency of LOH and 28 somatic mutations existed in the same group of patients. To prioritize mutations for alteration of protein functions and potentially involved in tumorigenesis, I selected 8 mutation sites based on their changes on the functional similarity residues of KRAB-ZFPs and performed alteration studies of cellular functions in lung cancer cells. When wild-type ZNF490 was over-expressed in three lung cancer cell lines, there was no change in cell proliferation rate but mainly in reduction of cell migration and some ZNF490 mutations loss the inhibitory effects. My results suggested ZNF490 may play a role in cell migration behavior. Currently, I am investigating altered functions of these ZNF490 mutations in tumorigenesis and evaluating their potentials as therapeutic target gene in NSCLC.
URI: http://hdl.handle.net/11455/23002
其他識別: U0005-0208201018575500
Appears in Collections:生命科學系所

Show full item record
 

Google ScholarTM

Check


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.