1. NCHU Institution Repository
  2. 生命科學院
  3. 生物醫學研究所
Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20163
標題: Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in mammalian cells
順鉑透過增強轉譯效率誘導hHR23蛋白表現
作者: 沈玉涵
Shen, Yu-Han
關鍵字: Rad23;順鉑;cisplatin;cancer;DNA repair;cytotoxicity;DNA修補;癌症;細胞毒性
出版社: 生物醫學研究所
引用: Altaha, R., Liang, X., Yu, J.J., and Reed, E. (2004). Excision repair cross complementing-group 1: gene expression and platinum resistance. Int J Mol Med 14, 959-970. Brignone, C., Bradley, K.E., Kisselev, A.F., and Grossman, S.R. (2004). A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway. Oncogene 23, 4121-4129. Chen, L., and Madura, K. (2006). Evidence for distinct functions for human DNA repair factors hHR23A and hHR23B. FEBS Lett 580, 3401-3408. Cortes-Sempere, M., Chattopadhyay, S., Rovira, A., Rodriguez-Fanjul, V., Belda-Iniesta, C., Tapia, M., Cejas, P., Machado-Pinilla, R., Manguan-Garcia, C., Sanchez-Perez, I., et al. (2009). MKP1 repression is required for the chemosensitizing effects of NF-kappaB and PI3K inhibitors to cisplatin in non-small cell lung cancer. Cancer Lett 286, 206-216. De Silva, I.U., McHugh, P.J., Clingen, P.H., and Hartley, J.A. (2000). Defining the roles of nucleotide excision repair and recombination in the repair of DNA interstrand cross-links in mammalian cells. Mol Cell Biol 20, 7980-7990. Doss-Pepe, E.W., Stenroos, E.S., Johnson, W.G., and Madura, K. (2003). Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis. Mol Cell Biol 23, 6469-6483. Ferry, K.V., Hamilton, T.C., and Johnson, S.W. (2000). Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF. Biochem Pharmacol 60, 1305-1313. Fousteri, M., and Mullenders, L.H. (2008). Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects. Cell Res 18, 73-84. Friedberg, E.C. (1995). Out of the shadows and into the light: the emergence of DNA repair. Trends Biochem Sci 20, 381. Fuertes, M.A., Alonso, C., and Perez, J.M. (2003). Biochemical modulation of Cisplatin mechanisms of action: enhancement of antitumor activity and circumvention of drug resistance. Chem Rev 103, 645-662. Furuta, T., Ueda, T., Aune, G., Sarasin, A., Kraemer, K.H., and Pommier, Y. (2002). Transcription-coupled nucleotide excision repair as a determinant of cisplatin sensitivity of human cells. Cancer Res 62, 4899-4902. Glockzin, S., Ogi, F.X., Hengstermann, A., Scheffner, M., and Blattner, C. (2003). Involvement of the DNA repair protein hHR23 in p53 degradation. Mol Cell Biol 23,8960-8969. Helleday, T., Petermann, E., Lundin, C., Hodgson, B., and Sharma, R.A. (2008). DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8, 193-204. Jamieson, E.R., and Lippard, S.J. (1999). Structure, Recognition, and Processing of Cisplatin-DNA Adducts. Chem Rev 99, 2467-2498. Kaur, M., Pop, M., Shi, D., Brignone, C., and Grossman, S.R. (2007). hHR23B is required for genotoxic-specific activation of p53 and apoptosis. Oncogene 26, 1231-1237. Koberle, B., Masters, J.R., Hartley, J.A., and Wood, R.D. (1999). Defective repair of cisplatin-induced DNA damage caused by reduced XPA protein in testicular germ cell tumours. Curr Biol 9, 273-276. Lebwohl, D., and Canetta, R. (1998). Clinical development of platinum complexes in cancer therapy: an historical perspective and an update. Eur J Cancer 34, 1522-1534. Li, L., Lu, X., Peterson, C., and Legerski, R. (1997). XPC interacts with both HHR23B and HHR23A in vivo. Mutat Res 383, 197-203. Malinge, J.M., Giraud-Panis, M.J., and Leng, M. (1999). Interstrand cross-links of cisplatin induce striking distortions in DNA. J Inorg Biochem 77, 23-29. Martin, L.P., Hamilton, T.C., and Schilder, R.J. (2008). Platinum resistance: the role of DNA repair pathways. Clin Cancer Res 14, 1291-1295. Ng, J.M., Vermeulen, W., van der Horst, G.T., Bergink, S., Sugasawa, K., Vrieling, H., and Hoeijmakers, J.H. (2003). A novel regulation mechanism of DNA repair by damage-induced and RAD23-dependent stabilization of xeroderma pigmentosum group C protein. Genes Dev 17, 1630-1645. Niedernhofer, L.J., Odijk, H., Budzowska, M., van Drunen, E., Maas, A., Theil, A.F., de Wit, J., Jaspers, N.G., Beverloo, H.B., Hoeijmakers, J.H., and Kanaar, R. (2004). The structure-specific endonuclease Ercc1-Xpf is required to resolve DNA interstrand cross-link-induced double-strand breaks. Mol Cell Biol 24, 5776-5787. Okuda, Y., Nishi, R., Ng, J.M., Vermeulen, W., van der Horst, G.T., Mori, T., Hoeijmakers, J.H., Hanaoka, F., and Sugasawa, K. (2004). Relative levels of the two mammalian Rad23 homologs determine composition and stability of the xeroderma pigmentosum group C protein complex. DNA Repair (Amst) 3, 1285-1295. Olaussen, K.A., Dunant, A., Fouret, P., Brambilla, E., Andre, F., Haddad, V., Taranchon, E., Filipits, M., Pirker, R., Popper, H.H., et al. (2006). DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355, 983-991. Rabik, C.A., and Dolan, M.E. (2007). Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev 33, 9-23. Sargent, R.G., Meservy, J.L., Perkins, B.D., Kilburn, A.E., Intody, Z., Adair, G.M.,Nairn, R.S., and Wilson, J.H. (2000). Role of the nucleotide excision repair gene ERCC1 in formation of recombination-dependent rearrangements in mammalian cells. Nucleic Acids Res 28, 3771-3778. Schauber, C., Chen, L., Tongaonkar, P., Vega, I., Lambertson, D., Potts, W., and Madura, K. (1998). Rad23 links DNA repair to the ubiquitin/proteasome pathway. Nature 391, 715-718. Selvakumaran, M., Pisarcik, D.A., Bao, R., Yeung, A.T., and Hamilton, T.C. (2003). Enhanced cisplatin cytotoxicity by disturbing the nucleotide excision repair pathway in ovarian cancer cell lines. Cancer Res 63, 1311-1316. Siddik, Z.H. (2003). Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22, 7265-7279. Stordal, B., and Davey, R. (2009). A systematic review of genes involved in the inverse resistance relationship between cisplatin and paclitaxel chemotherapy: role of BRCA1. Curr Cancer Drug Targets 9, 354-365. Sugasawa, K., Masutani, C., Uchida, A., Maekawa, T., van der Spek, P.J., Bootsma, D., Hoeijmakers, J.H., and Hanaoka, F. (1996). HHR23B, a human Rad23 homolog, stimulates XPC protein in nucleotide excision repair in vitro. Mol Cell Biol 16, 4852-4861. van der Spek, P.J., Eker, A., Rademakers, S., Visser, C., Sugasawa, K., Masutani, C., Hanaoka, F., Bootsma, D., and Hoeijmakers, J.H. (1996). XPC and human homologs of RAD23: intracellular localization and relationship to other nucleotide excision repair complexes. Nucleic Acids Res 24, 2551-2559. Wang, D., and Lippard, S.J. (2005). Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4, 307-320. Welsh, C., Day, R., McGurk, C., Masters, J.R., Wood, R.D., and Koberle, B. (2004). Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines. Int J Cancer 110, 352-361. Wu, X., Fan, W., Xu, S., and Zhou, Y. (2003). Sensitization to the cytotoxicity of cisplatin by transfection with nucleotide excision repair gene xeroderma pigmentosun group A antisense RNA in human lung adenocarcinoma cells. Clin Cancer Res 9, 5874-5879. Zhu, Q., Wani, G., Wani, M.A., and Wani, A.A. (2001). Human homologue of yeast Rad23 protein A interacts with p300/cyclic AMP-responsive element binding (CREB)-binding protein to down-regulate transcriptional activity of p53. Cancer Res 61, 64-70.
摘要: 
DNA damage agents are common therapeutic drugs to cancers. Unfortunately, DNA repair systems induced by anti-cancer drugs seem to play a key role in mediating drug resistance in cancer treatment. To evaluate the expression of DNA repair enzymes upon cancer treatment, lung adenocarcinoma cell line A549 was challenged with DNA damage agent, cisplatin. Cisplatin enhanced hHR23, an accessory protein involved in nucleotide-excision repair (NER) at early lesion-recognition step, protein expression with the dose-dependent and time-dependent manners. Low-dose cisplatin significantly induced hHR23 expression accompanied by the increased protein levels of p53, p21, and XPC. U0126 and LY294002 treatment attenuated hHR23 expression induced by cisplatin, indicating the MEK/ERK and PI3K/AKT signaling pathways were involved in the process. The mechanism underlying the MEK/ERK signaling on hHR23 protein expression relied on the increased translational initiation through the phosphorylation of eIF-4B. Moreover, knock-down of hHR23B by RNA interference decreased the repair of cisplatin-mediated DNA damage, cell survival, p53 and XPC induction. In contrast, overexpression of hHR23B enhanced the repair activity towards cisplatin-damaged DNA. Altogether, these results speculated that increased hHR23 by cisplatin is regulated by proliferative signaling pathways. Since cisplatin-induced DNA damage is mainly repaired by homologous recombination (HR) and NER, the role of hHR23B in HR pathway will be further investigated. In sum, the status of HR23 protein induction may be important in assessing patient prognosis in the clinical setting.

目前很多癌症藥物常藉由傷害細胞的DNA當作毒殺癌細胞的手段，但是癌症患者往往在化療藥物的療程中產生癌細胞抗藥性，使癌細胞不再受到藥物處理致死，其中一種原因是癌細胞會促進DNA修復系統的運作，使癌細胞在短時間內修復受損的DNA而免於死亡。 為了證實在癌症藥物治療時DNA修復酵素的表現程度，我們選用肺腺癌細胞株A549來處理一種傷害DNA的藥物”順鉑”，進一步的觀察到參與在早期核苷酸切除修復(Nucleotide excision repair, NER)步驟的hHR23/RAD23蛋白質表現程度隨著順鉑的劑量以及處理時間增加而增加。 低劑量的順鉑除了促進細胞中hHR23蛋白質的表現量之外也會增加p53、p21、和XPC的蛋白質的表現。 利用U0126與LY294002分別抑制MEK/ERK和PI3K/AKT訊息傳遞路徑，會減少順鉑所誘導的hHR23蛋白質表現。 另外，轉錄起使因子eIF-4B的聯酸化活化增加轉錄效率，促進MEK/ERK訊息路徑所調控的hHR23蛋白質表現。 重要的是利用RNA干擾技術靜默hHR23後處理順鉑會減少DNA修復能力、細胞存活率以及p53和XPC蛋白質的表現量，相反的，過度表現hHR23蛋白質會提升被順鉑傷害DNA之修補能力。 總結來說，我們看到順鉑藉由增加訊號傳遞路徑而誘導hHR23蛋白質表現，所以期許可以在臨床癌症病人做藥物治療時，藉由觀察hHR23蛋白質表現量來進行其癒後狀況的評估。 由於順鉑所引發的DNA傷害主要經由同源互換(homologous recombination ,HR)和核苷酸切除修復，所以接下來我們要進一步探討在同源互換中hHR23B蛋白質扮演的角色。
URI: http://hdl.handle.net/11455/20163
其他識別: U0005-0308201115581300
Appears in Collections:生物醫學研究所

Show full item record
 
TAIR Related Article

Google ScholarTM

Check


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