請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37278
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳小梨(Show-Li Chen) | |
dc.contributor.author | Yi-Hsuan Lin | en |
dc.contributor.author | 林奕瑄 | zh_TW |
dc.date.accessioned | 2021-06-13T15:23:13Z | - |
dc.date.available | 2013-08-14 | |
dc.date.copyright | 2008-08-14 | |
dc.date.issued | 2008 | |
dc.date.submitted | 2008-07-22 | |
dc.identifier.citation | Agoff, S. N., Hou, J., Linzer, D. I. & Wu, B. Regulation of the human hsp70 promoter by p53. Science 259, 84–87 (1993)
Amador V, Ge S, Santamaria PG, Guardavaccaro D, Paqano M. APC/C(Cdc20) controls the ubiquitin-mediated degradation of p21 in prometaphase. Mol Cell. 27, 462-473 (2007). Beck BD, Park SJ, Lee YJ, Roman Y, Hromas RA, Lee SH. Human Pso4 is a metnase (SETMAR)-binding partner that regulates metnase function in DNA repair. J Biol Chem. 283, 9023-30 (2008) . Berns EM, Foekens JA, van Staveren IL, van Putten WL, de Koning HY, Portengen H, Klijn JG. Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159, 11-18(1995). Budhram-Mahadeo, V. et al. p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor. J. Biol. Chem. 274, 15237–15244 (1999). Chen PH, Tsao YP, Wang CC, Chen SL. Nuclear receptor interaction protein, a coactivator of androgen receptor (AR), is regulated by AR and Sp1 to feed forward an activate its own gene expression through AR protein stability. Nuclear Acids Res. 36, 51-66 (2008). Datta B, Li B, Choubey D, Nallur G, Lengyel P. p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition. J. Biol. Chem. 271 275444-27545 (1996). Douglas AJ. Central noradrenergic mechanisms underlying acute stress responses of the Hypothalamo-pituitary-adrenal axis: adaptations through pregnancy and lactation. Stress. 8, 5-18 (2005). D’Souza S, Xin H, Walter S, Choubey D. The gene encoding p202, an interferon-inducible negative regulator of the p53 tumor suppressor, is a target of p53-mediated transcriptional repression. J. Biol. Chem. 276 298-305 (2001) Engelmann M, Landgraf R, Wotjak CT. The hypothalamic-neurohypophysial system regulates the hypothalamic-pituitary-adrenal axis under stress: an old concept revisited. Front Neuroendocrinol. 25 132-49 (2004). Fillippov V, Schmidt EL, Fillippov M, Duerksen-Hughes PJ. Splicing and splice factor SRp55 participate in the response to DNA damage by changing isoform ratios of target genes. Gene. In press (2008) Gaudray P, Szepetowski P, Escot C, Birnbaum D, Theillet C. DNA amplification at 11q13 in human cancer: from complexity to perplexity. Mutat Res 276, 317-328(1992). Gordan A. N., Fleagle J. T., Guthrie D., Parkin D. E., Gore M. E., Lacave A. J.. Recurrent epithelial ovarian carcinoma: a randomized phase Ⅲ study of pegylated liposomal doxorubicin versus topotecan. J. Clin. Oncol. 19, 3312-3322 (2001) Hebenstreit D, Giaisi M, Treiber M. K., Zhang XB, Mi HF, Hoeck JH, Andersen K. G., Krammer P. H., Duschl A, Li-Weber M. LEF-1 negatively controls interleukin-4 expression through a proximal promoter regulatory element. J. Biol. Chem. Papers In Press (2008) Hoffman, W. H., Biade, S., Zilfou, J. T., Chen, J. & Murphy, M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277, 3247–3257 (2002). Ingolia N. T. & Murray A. W. , Signal transduction: history matters. Science. 297, 948-949 (2002). Innocente, S. A. & Lee, J. M. p53 is a NF-Y- and p21-independent, Sp1-dependent repressor of cyclin B1 transcription. FEBS Lett. 579, 1001–1007 (2005). Johnson, R. A., Ince, T. A. & Scotto, K. W. Transcriptional repression by p53 through direct binding to a novel DNA element. J. Biol. Chem. 276, 27716–27720 (2001). Kaelin WG Jr. The p53 gene family. Oncogene. 18, 7701-7705 (1999). Kaluzova M, Kaluz S, Lerman MI, Stanbridge EJ. DNA damage is a prerequisite for p53-mediated proteasomal degradation of HIF-1α in hypoxic cells and downregulation of the hypoxia marker carbonic anhydrase IX. Mol. Cell. Biol. 24, 5757-5766 (2004). Kanaya, T. et al. Adenoviral expression of p53 represses telomerase activity through down-regulation of human telomerase reverse transcriptase transcription. Clin. Cancer Res. 6, 1239–1247 (2000). Kastan MB, Radin AI, Kuerbitz SJ, Onyekwere O, Wolkow CA, Civin CI, Stone KD, Woo T, Ravindranath Y, Craig RW. Levels of p53 protein increase with maturation in human hematopoietic cells. Cancer Res. 51, 4279-4286 (1991). Kastan MB, Onyekwere O, Sidransky D, Volgelstein B, Craig RW. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304-6311 (1991). Kern SE, Kinzler KW, Bruskin A, Jarosz D, Friedman P, Prives C, Volgelstein B. Identification of p53 as a sequence-specific DNA-binding protein. Science. 252, 1708-1711 (1991). Kidokoro T., Tanikawa C., Furukawa Y., Katagiri T., Nakamura Y., Matsuda K.. CDC20, a potential cancer therapeutic target, is negatively regulated by p53. Oncogene. (2007) Laurie NA, Schin-Shih C, Dyer MA. Targeting MDM2 and MDMX in retinoblastoma. Curr Cancer Drug Targes 7, 689-695 (2007) Lee, K. C., Crowe, A. J. & Barton, M. C. p53-mediated repression of alpha-fetoprotein gene expression by specific DNA binding. Mol. Cell. Biol. 19, 1279–1288 (1999). Lee S, Ha S, Chung M, Kim Y, Choi Y. Mouse DAM1 regulates pro-apoptotic activity of BLK in mammary epithelial cells. Cancer Lett 188, 121-126 (2002). Liu WS, Konduri S.D., Bansal S, Nayak B.K., Rajasekaran S.A., Karuppayil S.M., Rajasekaran A.K., Das G.M. Estrogen receptor-α binds p53 tumor suppressor protein directly and represses its function. J. Biol. Chem. 281, 9837-9840 (2006). Luo, J. et al. Acetylation of p53 augments its site-specific DNA binding both in vitro and in vivo. Proc. Natl Acad. Sci. USA 101, 2259–2264 (2004). Maass N, Rosel F, Schem C, Hitomi J, Jonat W, Nagasaki K.. Amplification of the BCAS2 gene at chromosome 1p13.3-21 in human primary breast cancer. Cancer Lett 185, 219-223 (2002). Mack D. H., Vartikar J, Pipas J. M., Lamins L. A. Nature. 363, 281-283 (1993). Mahajan KN, Mitchell BS. Role of human Pso4 in mammalian DNA repair and association with terminal deoxynucleotidyl transferase. Proc Natl Acad Sci U S A. 100, 10746-51 (2003) McKean-Cowdin R, Kolonel LN, Press MF, Pike MC, Henderson BE. Germ-line HER-2 variant and breast cancer risk by stage of disease. Cancer Res 61, 8393-8394 (2001). Murphy, M. et al. Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. Genes Dev. 13, 2490–2501 (1999). Nagasaki K, Maass N, Manabe T, Hanzawa H, Tsukada T, Kikuchi K, Yamaguchi K. Identification of a novel gene, DAM1, amplified at chromosome 1p13.3-21 region in human breast cancer cell lines. Cancer Lett 140, 219-226 (1999). Neubauer G, King A, Rappsilber J, Calvio C, Watson M, Ajuh P, Sleeman J, Lamond A, Mann M. Mass spectrometry and EST-database searching allows characterization of the multi-protein spliceosome complex. Nat Genet 20, 5-6 (1998). Noskov S Y, Wright J D, Lim C. Long-range effects of mutating R248 to Q/W in the p53 core domain. J. Phys. Chem. B. 106(50), 13047-13057 (2002). Ori, A. et al. p53 binds and represses the HBV enhancer: an adjacent enhancer element can reverse the transcription effect of p53. EMBO J. 17, 544–553 (1998). Osada, M. et al. Differential recognition of response elements determines target gene specificity for p53 and p63. Mol. Cell. Biol. 25, 6077–6089 (2005). Puszynski K, Hat B, Lipniacki T. Oscillations and bistability in the stochastic model of p53 regulation. J Theor Biol. In press (2008) Qi C, Zhu YT, Chang J, Yeldandi AV, Rao MS, Zhu YJ. Potentiation of estrogen receptor transcriptional activity by breast cancer amplified sequence 2. Biochem Biophys Res Commun 328, 393-398 (2005). Rahman-Roblick R, Roblick U. J., Hellman U, Conrotto P, Liu T, Becker S, Hirschberg D, Jornvall H, Auer G, Wiman K. G. p53 targets identified by protein expression profiling, . Proc. Natl Acad. Sci. USA 104, 5401-5406 (2007). Riley T., Sontag E., Chen P, Levine A. Tanscriptional control of human p53-regulated genes. Nature Rev. Mol. Cell Bio.9, 402-412 (2008) Sherr CJ. Principles of tumor suppression. Cell. 116, 235-246 (2004) Shiota M, Izumi H, Onitsuka T, Miyamoto N, Kashiwagi E, Kidani A, Hirano G, Takahashi M, Naito S and Kohno K. Twist and p53 reciprocally regulate target genes via direct interaction. Oncogene. In press(2008). Sun, Y., Zeng, X. R., Wenger, L., Firestein, G. S. & Cheung, H. S. P53 down-regulates matrix metalloproteinase-1 by targeting the communications between AP-1 and the basal transcription complex. J. Cell. Biochem. 92, 258–269 (2004). Todd R, Wong DT. Oncogenes. Anticancer Res. 19, 4729-4746 (1999). Toledo F, Wahl GM. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nat. Rev. Cancer. 6, 909-923 (2006). Wang Z, Fukuda S, Pelus LM. Survivin regulates the p53 tumor suppressor gene family. Oncogene. 23, 8146-8153 (2004). Worsham MJ, Pals G, Schouten JP, Miller F, Tiwari N, van Spaendonk R, Wolman SR. High-resolution mapping of molecular events associated with immortalization, transformation, and progression to breast cancer in the MCF10 model. Breast Cancer Res Treat 96, 177-86 (2006). Yun, J. et al. p53 negatively regulates cdc2 transcription via the CCAAT-binding NF-Y transcription factor. J. Biol. Chem. 274, 29677–29682 (1999). Zhang N, Kaur R, Lu X, Shen X, Li L, Legerski RJ. The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. J Biol Chem. 280, 40559-67 (2005). Zhang, Y. et al. Repression of hsp90β gene by p53 in UV irradiation-induced apoptosis of Jurkat cells. J. Biol. Chem. 279, 42545–42551 (2004 | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37278 | - |
dc.description.abstract | 新穎分子BCAS2已被發現在乳癌細胞株MCF7及MDA-MB-231,以及一些乳癌患者之臨床組織切片中,發現有基因放大或過度表現的的現象,並可能與乳癌細胞的侵襲性和遠端轉移有關。在本實驗室的研究中,發現默化BCAS2會導致MCF7細胞發生細胞凋亡,且細胞聚落形成能力降低。並發現BCAS2可以和抑癌蛋白p53結合,阻礙p53對下游目標基因如p21的轉錄活化,因此是一個p53的負向調控分子。
p53為細胞中最重要的抑癌分子之一,約有百分之五十以上的癌症被發現含有突變的p53,其餘大多數亦與p53的調控或訊息傳導途徑相關。p53由其轉錄調控因子的功能,辨認特定的DNA序列並與之結合,並影響目標基因的轉錄活化或抑制;或是藉由其下游基因間接調控其他基因。p53下游的基因在細胞週期、細胞凋亡、老化等細胞重要反應上,都扮演相當重要的角色。 在本研究中,我們發現BCAS2可受到p53的轉錄壓抑作用。在胚胎腎細胞株293T、乳癌細胞株MCF7及肺癌細胞株H1299中皆可觀察到p53的活化或大量表現,將導致BCAS2蛋白質表現量降低的現象。後續實驗則發現p53可壓抑BCAS2基因啟動子的活性,以及其mRNA的表現。染色質免疫沉澱分析的結果則說明p53可結合至BCAS2啟動子上。然而對於p53乃辨認BCAS2啟動子中哪一段序列做為結合位,目前仍尚未釐清。 本研究證明BCAS2是抑癌蛋白p53下游進行轉錄抑制的目標基因之一,然而先前研究中BCAS2亦為p53的負向調控因子,因此在BCAS2與p53之間存在著相互抑制的互動關係。在細胞處於正常環境下,BCAS2可以抑制p53的活性,使細胞得以正常地生長分裂;BCAS2的過量表現甚至可能是癌細胞中,p53無法正常作用的原因之一。然而一旦p53受到活化,則可以抑制BCAS2的表現,且此壓抑作用可使p53活性更加增強,形成正回饋的效果。未來可以此機制,作為癌症治療的目標之一;且BCAS2與p53之間的互動,也可以成為未來研究p53與負向調控因子之間的模式之一。 | zh_TW |
dc.description.abstract | A novel protein named BCAS2 has been reported overexpressed or gene amplified in breast cancer cell lines MCF7 and MDA-MB-231, as well as some of the clinical breast cancer samples. Overexpression of BCAS2 may associate with gaining of invasiveness and metastasis ability in breast cancer cells. Previous studies of our lab showed that silencing BCAS2 expression cause apoptosis in MCF7, and the colony-forming ability was dampened. BCAS2 was found to physically interact with the tumor suppressor p53.The interaction blocked the ability of p53 to transcribe target genes such as p21. Thus, we identified BCAS2 as a negative regulator of p53.
p53 is one of the most crucial tumor suppressors in cells. It was reported that p53 mutations occurred in more than fifty percent of human cancers, and most of the rest were associated with the regulation or signaling pathways of p53. As a transcription regulator, p53 can recognize and bind to a specific DNA sequence and therefore activate or repress the transcription activity of its target genes. Some indirect regulation can be achieved through its downstream pathway. The target genes of p53 participate in many central cellular events such as cell cycle regulation, apoptosis, and cell senescence. In this study, we demonstrated that p53 can transcriptionally repress BCAS2 expression. Overexpression or activation of p53 cause the decrease of protein expression of BCAS2 in human embryonic kidney cell 293T, the breast cancer cell line MCF7 and also the lung cancer cell line H1299. Further analysis showed the promoter activity of BCAS2 gene could be repressed by p53, followed by the decrease of mRNA expression. Chromatin immunoprecipitation was performed to verified that p53 associated with BCAS2 promoter. However, it has not yet been clarified which region within BCAS2 promoter could interact with p53. In this report we identified BCAS2 as one of the target gene of p53-mediated transcription repression. We have also shown that BCAS2 can negatively regulate the activity of p53 previously. Taking together, there might exist a reciprocal inhibition between p53 and BCAS2. Cells under normal condition can grow and proliferate normally in result of p53 inactivation by BCAS2 negative regulator. Moreover, overexpression of BCAS2 might therefore promote tumor progression. Nevertheless, once p53 is activated, it can repress BCAS2 expression, thus elevate its own activity. This mechanism can be a tumor therapeutic target in the future, as well as a model to investigate the relationship between p53 and some of its negative regulators. | en |
dc.description.provenance | Made available in DSpace on 2021-06-13T15:23:13Z (GMT). No. of bitstreams: 1 ntu-97-R95445120-1.pdf: 1538686 bytes, checksum: e3ef3a6ca19a5127e5fc1aedf18d2f08 (MD5) Previous issue date: 2008 | en |
dc.description.tableofcontents | 誌謝
中文摘要 英文摘要 緒論 致癌基因與抑癌基因 1 抑癌基因p53:結構與功能 3 p53的活化及對下游基因調控之機制 4 p53對目標基因之轉錄抑制 6 p53與下游基因的相互調控 7 BCAS2:文獻回顧 8 BCAS2對p53的負向調控 10 研究目的 12 材料及方法 14 結果 p53可降低BCAS2蛋白表現 27 p53可降低BCAS2的mRNA表現 28 p53可抑制BCAS2啟動子的活化 30 抑制p53可恢復BCAS2表現 32 p53可與BCAS2啟動子結合 32 尋找啟動子上可能的p53結合位 33 討論 36 參考文獻 43 圖附錄 48 | |
dc.language.iso | zh-TW | |
dc.title | 新穎蛋白BCAS2受抑癌分子p53轉錄調控之研究 | zh_TW |
dc.title | Study on the Transcription Regulation of Breast Cancer Amplified Sequence 2 (BCAS2) by p53 Tumor Suppressor | en |
dc.type | Thesis | |
dc.date.schoolyear | 96-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 董馨蓮,鄧述諄,謝小燕 | |
dc.subject.keyword | p53,BCAS2,轉錄壓抑,負調控因子,相互抑制, | zh_TW |
dc.subject.keyword | p53,BCAS2,transcription repression,negative regulator,reciprocal inhibition, | en |
dc.relation.page | 61 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2008-07-23 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-97-1.pdf 目前未授權公開取用 | 1.5 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。