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研究生:黃苡瑋
研究生(外文):Yi-wei Huang
論文名稱:探討人類神經母細胞瘤中NDPK調控c-myc基因表現的角色
論文名稱(外文):Regulation of c-myc transcription by NDPK in human neuroblastoma cells
指導教授:張玲張玲引用關係周振陽周振陽引用關係
指導教授(外文):Christina Ling ChangCheng-yang Chou
學位類別:碩士
校院名稱:國立成功大學
系所名稱:分子醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2008
畢業學年度:96
語文別:英文
論文頁數:42
中文關鍵詞:c-myc核苷二磷酸激酶A (NDPK-A)神經母細胞瘤癌症轉移轉譯
外文關鍵詞:c-mycNDPK-Aneuroblastomatumor metastasistranscription
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核苷二磷酸激酶A(NDPK-A)在神經母細胞瘤中扮演著促進轉移的角色,此腫瘤發生於神經脊為常見的兒童癌症。在神經母細胞瘤後期病人中NDPK-A過度表現或其S120G突變(NDPK-AS120G)已被偵測到,NDPK-A表現的改變在in vitro中導致神經元分化的缺失且促進細胞侵略性,而在動物體中促進神經母細胞瘤轉移。然而截至目前NDPK-A如何參與在癌症轉移的過程中尚未釐清。c-myc在神經脊發育中扮演著必要的角色,NDPK-A和NDPK-B具有88%的高度相似性,而NDPK-B已知參與c-myc基因轉譯調控。因此在這次的研究中,將利用人類神經母細胞瘤NB69細胞株探討在人類神經母細胞瘤中NDPK-A及NDPK-B如何分別及共同調控c-myc轉譯。利用c-myc promoter部分去除的突變以及氯黴素乙醯機轉移酶分析(CAT assay),發現在核酸酶高度敏感序列(NHE) III1 及NHE II具有負向順式調控片段 (cis-element),而正向順式調控片段位於NHE II2上游。儘管NDPK-A 或NDPK-AS120G 並不顯著影響c-myc promoter的活性,但兩者在NB69所衍生出的暫時性及穩定性轉染細胞中都可藉由NHE III1及NHE II抑制c-myc 轉譯去抑制作用。另一方面,NDPK-B藉由NHE III1以外的順式調控片段顯著活化c-myc promoter的活性。然而在NB69細胞中,NDPK-A或NDPK-AS120G 消除了受NDPK-B影響所導致的c-myc轉譯活化現象。我目前的發現首次證明了NDPK-A在c-myc轉譯調控上扮演和NDPK-B不同的角色,實驗結果顯示在NB69細胞中NDPK-A可能以非傳統方式藉由NHE III1以及位於NHE II上尚未確認的順式調控片段調控c-myc轉譯。研究結果顯示NDPK-A的過度表現或S120G突變可能藉由不正常調控c-myc轉譯影響神經脊發育而引致轉移性神經母細胞瘤。
Nucleoside diphosphate kinase (NDPK)-A behaves as a metastasis promoter in neuroblastoma, which is a common childhood tumor arising from the neural crest. Overexpression or S120G mutation of NDPK-A have been detected in patients with advanced stages of neuroblastoma. Such NDPK-A alterations abrogate neuronal differentiation and enhance cell invasiveness in vitro, while promoting neuroblastoma metastasis in animals. Currently it is unclear how NDPK-A is involved in tumor metastasis. However, it is known that c-myc plays an essential role in neural crest development. NDPK-A shares 88% identity with NDPK-B and the latter participates in the regulation of c-myc transcription. In this study, I therefore examined the individual and collaborative effects of NDPK-A and NDPK-B on c-myc transcriptional regulation in the human neuroblastoma NB69 cell model. Using c-myc promoter deletion mutants and the CAT assay, I found that negatively regulatory cis-elements were present in nuclease hypersensitive element (NHE) III1 and II regions, whereas positively regulatory cis-elements localized to upstream of NHE II2. Although NDPK-A or NDPK-AS120G did not significantly affect c-myc promoter activity, either protein inhibited c-myc transcriptional derepression via NHE III1 and NHE II in NB69-derived transient and stable transfectants. On the other hand, NDPK-B significantly activated the c-myc promoter activity likely via cis-elements other than NHE III1. However, NDPK-B activated c-myc transcription was abrogated by NDPK-A or NDPK-AS120G in NB69 cells. My current findings provide the first evidence showing that NDPK-A plays a different role from NDPK-B in c-myc transcriptional regulation. My results suggest that NDPK-A may modulate c-myc transcription via NHE III1 and yet-to-be identified cis-elements in NHE II in a non-conventional fashion in NB69 cells. It is possible that overexpression or S120G mutation of NDPK-A deregulates c-myc transcription, which in turn may affect neural crest development and lead to metastatic neuroblastoma.
Abstract i
Acknowledgement v
I. Introduction ` 1
I-1 Neuroblastoma 1
I-2 Human NM23/NDP Kinases 2
I-3 c-myc 3
I-4 NDPKs and c-myc transcription 4
I-5 Hypothesis 4
II. Materials and methods 5
II-1 pMyc-CAT reporter system and pMyc-CAT variants 5
II-2 Construction of various pMyc-CAT chimeric plasmids 5
II-3 Cell culture 6
II-4 Transient transfection 6
II-5 Western blot analysis 7
II-6 ��-Galactosidase (��-GAL) assay 7
II-7 Chloramphenicol acetyl transferase (CAT) assay 7
III. Results 9
III-1 Construction of various pMyc-CAT chimeric plasmids 9
III-2 Mapping regulatory elements in the c-myc promoter in human neuroblastoma NB69 cells 9
III-3 A high level of NDPK-A or NDPK-AS120G inhibits c-myc transcriptional derepression in NB69-derived transient and stable transfectants 10
III-4 NDPK-B activates c-myc transcription in human neuroblastoma NB69 cells
11
III-5 NDPK-A or NDPK-AS120G inhibits c-myc transcriptional activation mediated
by NDPK-B in NB69 derived transient transfectants 12
IV. Discussion 14
V. References 17
VI. Tables 24
Table 1. The stages of neuroblastoma defined by the International Neuroblastoma Staging System (INSS) and the correlation between stages and N-myc amplification 24
Table 2. The primers used for constructing of various pMyc-CAT chimeric plasmids
25
Table 3. The NB69 cell and NB69-derived transient and stable transfectants 26
VII. Figures 27
Figure 1. The pMyc-CAT reporter system and various pMyc-CAT chimeric plasmids
27
Figure 2. Mapping the regulatory elements of the c-myc promoter in human
neuroblastoma NB69 cells 29
Figure 3. Overexpression or S120G mutation of NDPK-A inhibits c-myc transcriptional derepression in transient transfectants derived from NB69 cells 30
Figure 4. Overexpression or S120G mutation of NDPK-A inhibits c-myc transcriptional derepression in NB69-derived stable transfectants 32
Figure 5. NDPK-B activates c-myc transcription in transiently transfected human neuroblastoma NB69 cells 33
Figure 6. NDPK-A or NDPK-AS120G inhibits NDPK-B induced c-myc transcriptional activation in transient transfectants derived from NB69 cells 35
VIII. Abbreviation list 37
IX. Appendix 39
Appendix 1. The human NM23/NDPK Kinase Family 39
Appendix 2. The phosphotransferase activity of NDPKs 40
Appendix 3. Primary sequence comparison and secondary structural elements of NDPK-A and NDPK-B proteins 41
Curriculum vitae 42
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