轉錄機轉的調控及蛋白質穩定性對於Sp1在肺癌形成中大量堆積所扮演的角色

陳思妤

doi:10.6844/NCKU.2010.00218

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轉錄機轉的調控及蛋白質穩定性對於Sp1在肺癌形成中大量堆積所扮演的角色

Role of Transcriptional Control and Protein Stability in Sp1 Accumulation during Lung Cancer Tumorigenesis

陳思妤 , Masters　　Advisor：洪建中　　

繁體中文 DOI： 10.6844/NCKU.2010.00218

肺癌； Sp1

Abstract │ Reference (57) │ Times Cited (9) │ Altmetrics

Abstract 〈TOP〉

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Ubiquitously expressed Sp1 regulates genes associated with cell growth, angiogenesis, apoptosis, cell proliferation, and control of cell cycle. Some of the target gene related to tumorigenesis including tumor oncogenes and suppressors such as VEGF and p53. Previous studies indicate that significantly elevated Sp1 level was observed in various tumor types and associated with a poor prognosis. Moreover, according to our previous data, lung tumor tissue has higher levels of Sp1 expression than normal tissue. Lung cancer is the leading cause of cancer-related mortality in Taiwan. It has low survival rates and all too often it is diagnosed at a late stage. Therefore, we are interest in studying the mechanism of Sp1 accumulation during lung tumorigenesis. In this study, we found that EGF treatment could induce Sp1 accumulation in lung primary cells,but not in lung cancer cell, A549 cells. Blocking Ras activity by FTI compound in EGF-treated primary cells or A549 cells attenuated Sp1 accumulation. These results imply that in tumorigenesis, activated Ras might contribute to Sp1 accumulation. To more address this conclusion, we established conditional lung cancer transgenic mice for further study. In this animal model, we found that KRAS activation is important to Sp1 accumulation in lung cancer formation indeed. Furthermore, not only increase in mRNA was observed but also the protein stability led to Sp1 accumulation. In vivo result indicated that Sp1 accumulate from the early period of K-ras activation, and maintain to the late period that the lung tissue has changed into atypical adenomatous hyperplasia. In addition, expression of Pin1 and cyclin B1, and interaction of Sp1 and RNF4 also increased during tumorigenesis. Finally, to study the role of Sp1 accumulation in lung cancer, a DNA binding inhibitor of Sp1 was intraperitoneally injected into the tumor-bearing mice Result indicated that tumor formation could be repressed significantly. Taken together, these data figure out that ras-pathway activated in tumorigenesis is important for Sp1 accumulation, and the effect of Sp1 in lung cancers is positive.

Reference ( 57 ) 〈TOP〉

Abdelrahim, M., C.H. Baker, J.L. Abbruzzese, and S. Safe. 2006. Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst. 98:855-68.
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Abdelrahim, M., and S. Safe. 2005. Cyclooxygenase-2 inhibitors decrease vascular endothelial growth factor expression in colon cancer cells by enhanced degradation of Sp1 and Sp4 proteins. Mol Pharmacol. 68:317-29.
連結：
Abdelrahim, M., R. Smith, 3rd, R. Burghardt, and S. Safe. 2004. Role of Sp proteins in regulation of vascular endothelial growth factor expression and proliferation of pancreatic cancer cells. Cancer Res. 64:6740-9.
連結：
Adhikary, S., and M. Eilers. 2005. Transcriptional regulation and transformation by Myc proteins. Nat Rev Mol Cell Biol. 6:635-45.
連結：
Black, A.R., J.D. Black, and J. Azizkhan-Clifford. 2001. Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol. 188:143-60.
連結：

Times Cited (9) 〈TOP〉

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