臺灣博碩士論文加值系統

在台灣，肺癌的死亡率高於其他類型的癌症，罹患肺癌的病人預後情況相當不理想，五年存活率僅15%，甚至早期發現並接受手術切除的病人，五年存活率僅70%，找出造成肺癌的分子機制有助於針對細胞訊息傳遞發展新的標靶治療，例如，在肺癌細胞中突變的Ras蛋白質會持續活化與細胞存活增生相關的訊息傳遞，進而幫助腫瘤生長與惡化，因此發展出針對Ras蛋白質的標靶治療。此外，過去的研究也發現許多人類癌症組織會過度表現特異性蛋白質 (Sp1)，而Sp1也跟腫瘤的惡性程度與不良的預後情形有關，此研究目的是探討Sp1在肺腫瘤發展中扮演的功能性角色，在此研究的第一個部分，我們首先建立可被四環黴素 (doxycycline) 激活KrasG12D並誘發肺腫瘤的基因轉殖鼠，探討Sp1在此動物模式中對肺部腫瘤生長與基因表現的影響，我們發現Sp1表現量在肺腫瘤有大量上升，同時在有注射Sp1抑制劑mithramycin A (MMA)的組別發現肺腫瘤有明顯的變小，伴隨著Sp1明顯的下降。接著我們釐清Sp1表現量在肺癌病人的臨床意義：相較於正常細胞與肺組織，我們發現Sp1在侵略性較差的肺癌細胞與第一期肺癌病人的檢體有顯著的增加；相較於肺癌早期，在高侵略性的肺癌細胞以及第四期肺癌病人的檢體，Sp1則有顯著的下降，但仍然比正常組織高。我們進一步地證明Sp1負向調控肺癌細胞的侵略性、移動能力與體內轉移的能力，在不同侵略性的肺癌細胞Sp1的表現量會有如此變化，是因為Sp1蛋白質的穩定性不同：在侵略性差的細胞，Sp1蛋白質比較穩定，不容易被降解，此外，在侵略性高的肺癌細胞，過度表現Sp1可誘發轉移抑制蛋白質，E-cadherin，的表現進而將-catenin固定在細胞膜附近，避免其入核而幫助癌細胞更惡化，綜合以上的證據，Sp1在肺癌早期會大量累積，在晚期則有下降的現象，這樣的現象分別幫助肺癌細胞在早期的增生以及在晚期的轉移。在第二部分我們探討會影響Sp1蛋白質穩定度的藥物樺木酸(betulinic acid)對肺腫瘤生長的影響，發現樺木酸藉由降低細胞內SENP1的表現量，造成Sp1的類泛素化(sumoylation) ，類泛素化的Sp1與RNF4產生交互作用，造成Sp1泛素化(ubiquitination)依賴性的蛋白質降解，此外，在KrasG12D誘發的肺癌轉殖鼠中，樺木酸與MMA皆明顯的抑制腫瘤生長，經由比較有無接受Sp1抑制劑的肺癌轉殖老鼠中帶有腫瘤的肺部基因表現，有542個基因在Sp1被抑制後受到影響，其中，鑑於cyclin A2與細胞增生與癌化相關，我們對其做進一步探討，不論是造成Sp1蛋白質降解的樺木酸，或是抑制Sp1結合到DNA能力的MMA，都顯著的降低cyclin A2的表現量，樺木酸的抗癌效果也進一步的在異種移植的小鼠模式被證實，而cyclin A2的減少降低了下游Rb蛋白質的磷酸化，最後造成細胞週期停滯在G2/M期，令人驚訝的是，Sp1基因默化(silence)的細胞對樺木酸產生明顯的抗藥性，這些發現釐清了樺木酸對Sp1的影響機制，以及證實了Sp1的存在對樺木酸的抗癌效果極為重要。

Lung cancer is the leading cause of cancer mortality and the prognosis for lung carcinoma patients is generally poor (5-yr survival rate 〈 15%) in Taiwan, even if diagnosed and treated successfully, patients with early stage of lung carcinoma have a 5-year survival rate of only 70% after surgical resection. Understanding of the molecular attributes of lung tumors provides clues to develop the therapy targeting defective cellular pathways for lung cancer, such as Ras proteins which activates Ras/Raf-1/mitogen-activated protein kinase pathway. The transcription factor, specificity protein (Sp) 1 was found to be overexpressed in several human cancers and the Sp1 levels correlated with tumor grade/stage and poor prognosis. The overall objective of this study is to identify the functional role and potential contribution of Sp1 in lung tumorigenesis. In the first section, we showed that the Sp1 level was highly increased and required for lung tumor growth in transgenic mice bearing KrasG12D-induced lung tumors under the control of doxycycline. Furthermore, the Sp1 level was highly upreguated in lung adenocarcinoma cells with low invasiveness and in patients with stage I lung cancer. We also demonstrated that Sp1 was downregulated in lung adenocarcinoma cells with high invasiveness and in patients with stage IV lung adenocarcinoma. In particular, Sp1 expression in highly invasive lung adenocarcinoma cells is still significantly higher than that in normal lung fibroblast. Moreover, Sp1 inversely regulated migration, invasion and metastasis of lung adenocarcinoma cells in vivo. In addition, a decrease in the Sp1 level in highly invasive lung adenocarcinoma cells resulted from instability of the Sp1 protein. Furthermore, overexpression of Sp1 in highly invasive lung adenocarcinoma cells increased expression of E-cadherin, a suppressor of metastasis, and attenuated the translocation of -catenin into the cellular nucleus which leads to tumor malignancy. Taken together, Sp1 level accumulates strongly in early stage and then declines in late stage, which are important for lung cancer cell proliferation and metastasis, respectively, during tumorigenesis. In the second section, we evaluated the effect of an anti-tumor drug, betulinic acid (BA), targeting Sp1 on lung cancer in vitro and in vivo. Herein, we found that BA treatment increased the sumoylation of Sp1 by inhibiting SENP1 expression and the recruitment of E3 ligase, RNF4, followed by resulting in ubiquitination-mediated degradation in a 26S proteosome-dependent pathway. In addition, both of BA and mithramycin A (MMA) treatment inhibited lung tumor growth, and downregulated Sp1 protein expression in KrasG12D-induced lung cancers of bitransgenic mice. In the study of gene expression profiles of KrasG12D-induced lung cancers of bitransgenic mice with and without Sp1 inhibition, 542 of genes were affected by repressing Sp1 expression. One of these important genes, cyclin A2 (CCNA2), was addressed deeply to indicate that CCNA2 expression was attenuated by BA and MMA treatments through decreasing Sp1 protein stability and DNA binding affinity, respectively. Downregulation of CCNA2 led to decrease in Rb phosphorylation and to causing cell cycle G2/M-arrest. BA-mediated cellular Sp1 degradation and antitumor effect were also further confirmed in xenograft mouse model by using H1299 cells. Knock down of Sp1 in lung cancer cells attenuated the anti-cell growth effect of BA. Taken together, this study clarified the mechanism of BA-mediated Sp1 degradation, and identified that Sp1 level plays a pivotal role in BA-induced repression of lung cancer growth.

中文摘要 I
Abstract III
Acknowledgements V
Contents VI
Abbreviations XII
Introduction
I. Lung cancer
A. Epidemiology and histological classification 1
B. Pathogenesis 1
C. Metastasis 3
D. Common genetic abnormalities in lung cancer 3
E. Kras mutation in lung cancer 5
F. Transcription factors in lung cancer 6
II. Specificity protein (Sp) 1
A. Basic concept of Sp1 8
B. Target genes for cellular functions 8
C. Post translational modifications of Sp1 9
D. Sp1 in human disease 10
E. The possible role of Sp1 in lung cancer 11
III. Anti-tumor drugs targeting Sp1
A. Overview 12
B. Mithramycin A (MMA) 13
C. Betulinic acid (BA) 13
IV. Research aims and significance of this study 14
Materials and Methods
Materials 16
Methods 22
Results
Chapter 1: Sp1 is involved in lung tumor growth, but represses lung tumor metastasis
Rationale 31
Experimental results
1. The role of Sp1 in lung tumor growth 32
2. The clinical significance of Sp1 in lung cancer patients 33
3. The role of Sp1 in metastasis of lung tumor cells 35
4. The mechanism underlying the alteration of the Sp1 level in lung adenocarcinoma cells with different invasiveness 37
5. The mechanism of Sp1-mediated repression in metastasis 38
6. Effect of MMA on CL1-0 cells 40
7. Summary I 40
Figures and Table
Figure 1. Kras inhibition by FTI-276 decreases the protein level of Sp1 in
A549 cells. 42
Figure 2. The model of Kras4bG12D induced lung tumorigenesis under the control of doxycycline. 43
Figure 3. MMA prevents doxycycline-induced pathological changes in the lungs of bitransgenic mice. 44
Figure 4. Constitutively activated Kras triggered by doxycycline induces lung tumor formation, and MMA attenuates this phenomenon. 46
Figure 5. H-score for the signals of Kras, pErk, PCNA and CCSP. 47
Figure 6. Sp1 expression is negatively correlated with survival of lung adenocarcinoma patients. 48
Figure 7. Sp1 negatively regulates invasive and migratory abilities of lung cancer cells. 50
Figure 8. Sp1 overexpression promotes proliferation of CL1-5, not 1-0
and 1-1 cells. 52
Figure 9. Sp1 knockdown enhances invasive and migratory abilities of
CL1-0 cells. 53
Figure 10. Sp1 suppresses lung adenocarcinoma cell metastasis in vivo. 55
Figure 11. Downregulation of Sp1 expression in highly invasive lung adenocarcinoma cells is caused by instability of Sp1 protein. 57
Figure 12. Sp1 positively regulates E-cadherin expression and attenuates the translocation of -catenin into the cell nucleus. 59
Figure 13. Effect of MMA on CL1-0 cells. 62
Figure 14. The illustration explaining that Sp1 expression regulates lung tumor progression. 63
Table 1. Characteristic of 118 patients with lung adenocarcinoma analyzed by immunohistochemical staining. 65
Chapter 2: Betulinic acid inhibits lung tumor growth through inducing sumoylation- and ubiquitination-dependent Sp1 degradation
Rationale 66
Experimental results
8. Effect of BA on the Sp1 level in cancer cells 67
9. Effect of BA on lung tumor growth in vitro and in vivo 68
10. The role of Sp1 in BA-induced apoptosis in lung cancer cells 69
11. Identification of possible Sp1-regulated genes in lung tumorigenesis 70
12. Effect of BA on the expression of Sp1 target gene, cyclin A2 (CCNA2) 71
13. The consequence of BA-suppressed Sp1-regulated CCNA2 expression 71
14. Summary II 72
Figures and Table
Figure 15. Effects of BA on Sp1 protein degradation and SENP1 expression. 74
Figure 16. Effect of BA on the protein level of SENP1 in A549 cells. 76
Figure 17. Effect of BA on cellular proliferation and Sp1 expression in lung adenocarcinoma cells. 77
Figure 18. Effect of BA and MMA on lung tumor growth in vivo. 78
Figure 19. Effect of Sp1 knockdown on BA-mediated antitumor effect in lung adenocarcinoma cells. 80
Figure 20. Identification of Sp1-regulated gene expression related to proliferation in KrasG12D-driven lung tumorigenesis. 82
Figure 21. Heatmap of microarray data show that 542 genes are possibly regulated by Sp1 in the growth of lung tumor. 84
Figure 22. Effect of BA on Sp1-regulated CCNA2 expression in lung adenocarcinomas. 85
Figure 23. Effects of BA on RB phosphorylation and cell cycle progression in lung adenocarcinomas. 87
Figure 24. The proposed model illustrates that BA induces proteasome-dependent degradation of Sp1. 89
Table 2. Characteristics of 36 patients with lung adenocarcinomas analyzed by immunohistochemical staining. 90
Table 3. Microarray analysis reveals that 40 of well-known genes related to proliferation are regulated by Sp1 in lung tumor growth. 91
Discussion
1. The possible role of Sp1 in metastasis 96
2. Whether MMA-mediated Sp1 downregulation affects metastasis ? 96
3. Drugs targeting Sp1 may only benefit patients with early stage of lung cancer. 97
4. Post translational modification modulates Sp1 protein stability in lung cancer cells with different invasiveness. 97
5. Sp1 may regulate metastasis through controlling E-cadherin expression. 98
6. Different outcomes of Sp1 overexpression in highly invasive lung adenocarcinoma cells. 98
7. Sp1 attenuates -catenin translocation into cell nucleus for tumor malignancy. 99
8. Why is the decrease of the Sp1 level required for BA-induced cellular
apoptosis ? 99
9. The possible mechanism of BA-induced Sp1 degradation in a proteasome-dependent manner. 100
10. Sp1-regulated target genes expressions are important for lung tumor growth. 100
Conclusions 102
Figure 25. Sp1 promotes lung tumor growth through cyclin A2/Rb cascade, and inversely regulates metastasis through inducing E-cadherin expression. 103
References 104
Appendixes
Appendix 1 131
Appendix 2 132
Appendix 3 133
Appendix 4 134
Appendix 5 135
Appendix 5 (Continue) 136
Curriculum vitae 137
Published thesis (First author) 138

Abdelrahim, M., Baker, C. H., Abbruzzese, J. L., and Safe, S. (2006). Tolfenamic acid and pancreatic cancer growth, angiogenesis, and Sp protein degradation. J Natl Cancer Inst 98, 855-868.
Agarwal, S., Achari, C., Praveen, D., Roy, K. R., Reddy, G. V., and Reddanna, P. (2009). Inhibition of 12-LOX and COX-2 reduces the proliferation of human epidermoid carcinoma cells (A431) by modulating the ERK and PI3K-Akt signalling pathways. Exp Dermatol 18, 939-946.
Ahlgren, R., Suske, G., Waterman, M. R., and Lund, J. (1999). Role of Sp1 in cAMP-dependent transcriptional regulation of the bovine CYP11A gene. J Biol Chem 274, 19422-19428.
Alakurtti, S., Makela, T., Koskimies, S., and Yli-Kauhaluoma, J. (2006). Pharmacological properties of the ubiquitous natural product betulin. Eur J Pharm Sci 29, 1-13.
Antonysamy, M. A., Moticka, E. J., and Ramkumar, V. (1995). Adenosine acts as an endogenous modulator of IL-2-dependent proliferation of cytotoxic T lymphocytes. J Immunol 155, 2813-2821.
Armstrong, A. J., Gebre, A. K., Parks, J. S., and Hedrick, C. C. (2010). ATP-binding cassette transporter G1 negatively regulates thymocyte and peripheral lymphocyte proliferation. J Immunol 184, 173-183.
Badie, C., Bourhis, J., Sobczak-Thepot, J., Haddada, H., Chiron, M., Janicot, M., Janot, F., Tursz, T., and Vassal, G. (2000). p53-dependent G2 arrest associated with a decrease in cyclins A2 and B1 levels in a human carcinoma cell line. Br J Cancer 82, 642-650.
Baki, L., Shioi, J., Wen, P., Shao, Z., Schwarzman, A., Gama-Sosa, M., Neve, R., and Robakis, N. K. (2004). PS1 activates PI3K thus inhibiting GSK-3 activity and tau overphosphorylation: effects of FAD mutations. EMBO J 23, 2586-2596.
Berger, T., Cheung, C. C., Elia, A. J., and Mak, T. W. (2010). Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proc Natl Acad Sci U S A 107, 2995-3000.
Berlin, Y. U., Kiseleva, O. A., Kolosov, M. N., Shemyakin, M. M., and Soifer, V. S. (1968). Aureolic acid group of anti-tumour antibiotics. Nature 218, 193-194.
Berthet, C., Aleem, E., Coppola, V., Tessarollo, L., and Kaldis, P. (2003). Cdk2 knockout mice are viable. Curr Biol 13, 1775-1785.
Black, A. R., Black, J. D., and Azizkhan-Clifford, J. (2001). Sp1 and kruppel-like factor family of transcription factors in cell growth regulation and cancer. J Cell Physiol 188, 143-160.
Blume, S. W., Snyder, R. C., Ray, R., Thomas, S., Koller, C. A., and Miller, D. M. (1991). Mithramycin inhibits SP1 binding and selectively inhibits transcriptional activity of the dihydrofolate reductase gene in vitro and in vivo. J Clin Invest 88, 1613-1621.
Bos, J. L. (1989). Ras Oncogenes in Human Cancer - a Review. Cancer Res 49, 4682-4689.
Bouwman, P., and Philipsen, S. (2002). Regulation of the activity of Sp1-related transcription factors. Mol Cell Endocrinol 195, 27-38.
Boyle, K. B., Hadaschik, D., Virtue, S., Cawthorn, W. P., Ridley, S. H., O'Rahilly, S., and Siddle, K. (2009). The transcription factors Egr1 and Egr2 have opposing influences on adipocyte differentiation. Cell Death Differ 16, 782-789.
Brambilla, E., and Gazdar, A. (2009). Pathogenesis of lung cancer signalling pathways: roadmap for therapies. Eur Respir J 33, 1485-1497.
Brambilla, E., Gazzeri, S., Moro, D., Lantuejoul, S., Veyrenc, S., and Brambilla, C. (1999). Alterations of Rb pathway (Rb-p16INK4-cyclin D1) in preinvasive bronchial lesions. Clin Cancer Res 5, 243-250.
Bremnes, R. M., Veve, R., Hirsch, F. R., and Franklin, W. A. (2002). The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer 36, 115-124.
Bruch-Gerharz, D., Schnorr, O., Suschek, C., Beck, K. F., Pfeilschifter, J., Ruzicka, T., and Kolb-Bachofen, V. (2003). Arginase 1 overexpression in psoriasis: limitation of inducible nitric oxide synthase activity as a molecular mechanism for keratinocyte hyperproliferation. Am J Pathol 162, 203-211.
Bruyere, F., Namdarian, B., Corcoran, N. M., Pedersen, J., Ockrim, J., Voelzke, B. B., Mete, U., Costello, A. J., and Hovens, C. M. (2010). Snail expression is an independent predictor of tumor recurrence in superficial bladder cancers. Urol Oncol 28, 591-596.
Bu, Y., Gao, L., and Gelman, I. H. (2011). Role for transcription factor TFII-I in the suppression of SSeCKS/Gravin/Akap12 transcription by Src. Int J Cancer 128, 1836-1842
Cawley, S., Bekiranov, S., Ng, H. H., Kapranov, P., Sekinger, E. A., Kampa, D., Piccolboni, A., Sementchenko, V., Cheng, J., Williams, A. J., et al. (2004). Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116, 499-509.
Chadalapaka, G., Jutooru, I., Chintharlapalli, S., Papineni, S., Smith, R., 3rd, Li, X., and Safe, S. (2008). Curcumin decreases specificity protein expression in bladder cancer cells. Cancer Res 68, 5345-5354.
Chan, Q. K., Lam, H. M., Ng, C. F., Lee, A. Y., Chan, E. S., Ng, H. K., Ho, S. M., and Lau, K. M. (2010). Activation of GPR30 inhibits the growth of prostate cancer cells through sustained activation of Erk1/2, c-jun/c-fos-dependent upregulation of p21, and induction of G(2) cell-cycle arrest. Cell Death Differ 17, 1511-1523.
Chang, H. C., Liu, L. T., and Hung, W. C. (2004). Involvement of histone deacetylation in ras-induced down-regulation of the metastasis suppressor RECK. Cell Signal 16, 675-679.
Chao, Y. C., Pan, S. H., Yang, S. C., Yu, S. L., Che, T. F., Lin, C. W., Tsai, M. S., Chang, G. C., Wu, C. H., Wu, Y. Y., et al. (2009). Claudin-1 is a metastasis suppressor and correlates with clinical outcome in lung adenocarcinoma. Am J Respir Crit Care Med 179, 123-133.
Chapman, A. D., and Kerr, K. M. (2000). The association between atypical adenomatous hyperplasia and primary lung cancer. Br J cancer 83, 632-636.
Chen, J., Ye, L., Xie, F., Yang, Y., Zhang, L., and Jiang, W. G. (2010). Expression of bone morphogenetic protein 7 in lung cancer and its biological impact on lung cancer cells. Anticancer Res 30, 1113-1120.
Chen, W., Li, Z., Bai, L., and Lin, Y. (2011). NF-kappaB in lung cancer, a carcinogenesis mediator and a prevention and therapy target. Front Biosci 16, 1172-1185.
Chen, W., Wang, X., Bai, L., Liang, X., Zhuang, J., and Lin, Y. (2008). Blockage of NF-kappaB by IKKbeta- or RelA-siRNA rather than the NF-kappaB super-suppressor IkappaBalpha mutant potentiates adriamycin-induced cytotoxicity in lung cancer cells. J Cell Biochem 105, 554-561.
Chintharlapalli, S., Papineni, S., Lei, P., Pathi, S., and Safe, S. (2011). Betulinic acid inhibits colon cancer cell and tumor growth and induces proteasome-dependent and -independent downregulation of specificity proteins (Sp) transcription factors. BMC cancer 11, 371.
Chintharlapalli, S., Papineni, S., Ramaiah, S. K., and Safe, S. (2007). Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 67, 2816-2823.
Christensen, M. A., Zhou, W., Qing, H., Lehman, A., Philipsen, S., and Song, W. (2004). Transcriptional regulation of BACE1, the beta-amyloid precursor protein beta-secretase, by Sp1. Mol Cell Biol 24, 865-874.
Chu, Y. W., Yang, P. C., Yang, S. C., Shyu, Y. C., Hendrix, M. J., Wu, R., and Wu, C. W. (1997). Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. Am J Respir Cell Mol Biol 17, 353-360.
Chuang, J. Y., Chang, W. C., and Hung, J. J. (2011). Hydrogen peroxide induces Sp1 methylation and thereby suppresses cyclin B1 via recruitment of Suv39H1 and HDAC1 in cancer cells. Free Radic Biol Med 51, 2309-2318.
Chuang, J. Y., Wang, Y. T., Yeh, S. H., Liu, Y. W., Chang, W. C., and Hung, J. J. (2008). Phosphorylation by c-Jun NH2-terminal kinase 1 regulates the stability of transcription factor Sp1 during mitosis. Mol Biol Cell 19, 1139-1151.
Chuang, J. Y., Wu, C. H., Lai, M. D., Chang, W. C., and Hung, J. J. (2009). Overexpression of Sp1 leads to p53-dependent apoptosis in cancer cells. Int J Cancer 125, 2066-2076.
Collins, L. G., Haines, C., Perkel, R., and Enck, R. E. (2007). Lung cancer: diagnosis and management. Am Fam Physician 75, 56-63.
Conway, T. F., Jr., Sabel, M. S., Sugano, M., Frelinger, J. G., Egilmez, N. K., Chen, F., and Bankert, R. B. (2000). Growth of human tumor xenografts in SCID mice quantified using an immunoassay for tumor marker protein in serum. J Immunol Methods 233, 57-65.
Cram, E. J., Liu, B. D., Bjeldanes, L. F., and Firestone, G. L. (2001). Indole-3-carbinol inhibits CDK6 expression in human MCF-7 breast cancer cells by disrupting Sp1 transcription factor interactions with a composite element in the CDK6 gene promoter. J Biol Chem 276, 22332-22340.
DeFino, M. C., Wacker, J. L., Lyssand, J. S., Wang, E. H., and Hague, C. (2010). Differential regulation of GPR54 transcription by specificity protein-1 and partial estrogen response element in mouse pituitary cells. Biochem Biophys Res Commun 393, 603-608.
Denlinger, C. E., Ikonomidis, J. S., Reed, C. E., and Spinale, F. G. (2010). Epithelial to mesenchymal transition: the doorway to metastasis in human lung cancers. J Thorac Cardiovasc Surg 140, 505-513.
Diamandis, E. P., Goodglick, L., Planque, C., and Thornquist, M. D. (2011). Pentraxin-3 Is a Novel Biomarker of Lung Carcinoma. Clin Cancer Res 17, 2395-2399.
Duverger, V., Murphy, A. M., Sheehan, D., England, K., Cotter, T. G., Hayes, I., and Murphy, F. J. (2004). The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF). Br J Cancer 90, 2025-2031.
Ehrhardt, H., Fulda, S., Fuhrer, M., Debatin, K. M., and Jeremias, I. (2004). Betulinic acid-induced apoptosis in leukemia cells. Leukemia 18, 1406-1412.
Emili, A., Greenblatt, J., and Ingles, C. J. (1994). Species-specific interaction of the glutamine-rich activation domains of Sp1 with the TATA box-binding protein. Mol Cell Biol 14, 1582-1593.
Esteve, P. O., Chin, H. G., and Pradhan, S. (2007). Molecular mechanisms of transactivation and doxorubicin-mediated repression of survivin gene in cancer cells. J Biol Chem 282, 2615-2625.
Firestone, G. L., and Bjeldanes, L. F. (2003). Indole-3-carbinol and 3-3'-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. J Nutr 133, 2448S-2455S.
Fisher, G. H., Wellen, S. L., Klimstra, D., Lenczowski, J. M., Tichelaar, J. W., Lizak, M. J., Whitsett, J. A., Koretsky, A., and Varmus, H. E. (2001b). Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 15, 3249-3262.
Fojas de Borja, P., Collins, N. K., Du, P., Azizkhan-Clifford, J., and Mudryj, M. (2001). Cyclin A-CDK phosphorylates Sp1 and enhances Sp1-mediated transcription. The EMBO journal 20, 5737-5747.
Forbes, S., Clements, J., Dawson, E., Bamford, S., Webb, T., Dogan, A., Flanagan, A., Teague, J., Wooster, R., Futreal, P. A., and Stratton, M. R. (2006). The Ras antagonist S-farnesylthiosalicylic acid induces inhibition of MAPK activation. Br J Cancer 94, 318-322.
Frixen, U. H., Behrens, J., Sachs, M., Eberle, G., Voss, B., Warda, A., Lochner, D., and Birchmeier, W. (1991). E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells. J Cell Biol 113, 173-185.
Fulda, S. (2008). Betulinic Acid for cancer treatment and prevention. Int J Mol Sci 9, 1096-1107.
Fulda, S., Friesen, C., Los, M., Scaffidi, C., Mier, W., Benedict, M., Nunez, G., Krammer, P. H., Peter, M. E., and Debatin, K. M. (1997). Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res 57, 4956-4964.
Fulda, S., Jeremias, I., Steiner, H. H., Pietsch, T., and Debatin, K. M. (1999). Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells. Int J Cancer 82, 435-441.
GanaWeisz, M. L., Haklai, R., Marciano, D., Egozi, Y., BenBaruch, G., and Kloog, Y. (1997). The Ras antagonist S-farnesylthiosalicylic acid induces inhibition of MAPK activation. Biochem Biophys Res Commun 239, 900-904.
Gazdar, A. F., Shigematsu, H., Herz, J., and Minna, J. D. (2004). Mutations and addiction to EGFR: the Achilles 'heal' of lung cancers? Trends Mol Med 10, 481-486.
Gazzeri, S., Della Valle, V., Chaussade, L., Brambilla, C., Larsen, C. J., and Brambilla, E. (1998). The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. Cancer Res 58, 3926-3931.
Giatromanolaki, A., Koukourakis, M. I., Sivridis, E., Turley, H., Talks, K., Pezzella, F., Gatter, K. C., and Harris, A. L. (2001). Relation of hypoxia inducible factor 1 alpha and 2 alpha in operable non-small cell lung cancer to angiogenic/molecular profile of tumours and survival. Br J cancer 85, 881-890.
Gorska, M. M., Stafford, S. J., Cen, O., Sur, S., and Alam, R. (2004). Unc119, a novel activator of Lck/Fyn, is essential for T cell activation. J Exp Med 199, 369-379.
Grinstein, E., Jundt, F., Weinert, I., Wernet, P., and Royer, H. D. (2002). Sp1 as G1 cell cycle phase specific transcription factor in epithelial cells. Oncogene 21, 1485-1492.
Guichard, S. M., Else, R., Reid, E., Zeitlin, B., Aird, R., Muir, M., Dodds, M., Fiebig, H., Sadler, P. J., and Jodrell, D. I. (2006). Anti-tumour activity in non-small cell lung cancer models and toxicity profiles for novel ruthenium(II) based organo-metallic compounds. Biochem Pharmacol 71, 408-415.
Herbst, R. S., Heymach, J. V., and Lippman, S. M. (2008). Lung cancer. N Engl J Med 359, 1367-1380.
Hirsch, F. R., Varella-Garcia, M., Bunn, P. A., Jr., Di Maria, M. V., Veve, R., Bremmes, R. M., Baron, A. E., Zeng, C., and Franklin, W. A. (2003). Epidermal growth factor receptor in non-small-cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21, 3798-3807.
Hockel, M., Schlenger, K., Aral, B., Mitze, M., Schaffer, U., and Vaupel, P. (1996). Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res 56, 4509-4515.
Hollmann, A., Aloyz, R., Baker, K., Dirnhofer, S., Owens, T., Sladek, R., and Tzankov, A. (2010). Vav-1 expression correlates with NFkappaB activation and CD40-mediated cell death in diffuse large B-cell lymphoma cell lines. Hematol Oncol 28, 142-150.
Hommura, F., Furuuchi, K., Yamazaki, K., Ogura, S., Kinoshita, I., Shimizu, M., Moriuchi, T., Katoh, H., Nishimura, M., and Dosaka-Akita, H. (2002). Increased expression of beta-catenin predicts better prognosis in nonsmall cell lung carcinomas. Cancer 94, 752-758.
Howie, D., Okamoto, S., Rietdijk, S., Clarke, K., Wang, N., Gullo, C., Bruggeman, J. P., Manning, S., Coyle, A. J., Greenfield, E., et al. (2002). The role of SAP in murine CD150 (SLAM)-mediated T-cell proliferation and interferon gamma production. Blood 100, 2899-2907.
Hung, J. J., Wang, Y. T., and Chang, W. C. (2006). Sp1 deacetylation induced by phorbol ester recruits p300 to activate 12(S)-lipoxygenase gene transcription. Mol Cell Biol 26, 1770-1785.
Hung, T. L., Chen, F. F., Liu, J. M., Lai, W. W., Hsiao, A. L., Huang, W. T., Chen, H. H., and Su, W. C. (2003). Clinical evaluation of HER-2/neu protein in malignant pleural effusion-associated lung adenocarcinoma and as a tumor marker in pleural effusion diagnosis. Clin Cancer Res 9, 2605-2612.
Ibanez, A., Rio, P., Casado, J. A., Bueren, J. A., Fernandez-Luna, J. L., and Pipaon, C. (2009). Elevated levels of IL-1beta in Fanconi anaemia group A patients due to a constitutively active phosphoinositide 3-kinase-Akt pathway are capable of promoting tumour cell proliferation. Biochem J 422, 161-170.
Innocente, S. A., and Lee, J. M. (2005). p53 is a NF-Y- and p21-independent, Sp1-dependent repressor of cyclin B1 transcription. FEBS Lett 579, 1001-1007.
Ioannou, M., Papamichali, R., Kouvaras, E., Mylonis, I., Vageli, D., Kerenidou, T., Barbanis, S., Daponte, A., Simos, G., Gourgoulianis, K., and Koukoulis, G. K. (2009). Hypoxia inducible factor-1 alpha and vascular endothelial growth factor in biopsies of small cell lung carcinoma. Lung 187, 321-329.
Jackson, E. L., Willis, N., Mercer, K., Bronson, R. T., Crowley, D., Montoya, R., Jacks, T., and Tuveson, D. A. (2001). Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev 15, 3243-3248.
Jacoby, J. J., Erez, B., Korshunova, M. V., Williams, R. R., Furutani, K., Takahashi, O., Kirkpatrick, L., Lippman, S. M., Powis, G., O'Reilly, M. S., and Herbst, R. S. (2010). Treatment with HIF-1alpha antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice. J Thorac Onco 5, 940-949.
Jansen, B., Schlagbauer-Wadl, H., Kahr, H., Heere-Ress, E., Mayer, B. X., Eichler, H. G., Pehamberger, H., Gana-Weisz, M., Ben-David, E., Kloog, Y., and Wolff, K. (1999). Novel Ras antagonist blocks human melanoma growth. Proc Natl Acad Sci U S A 96, 14019-14024.
Jeanmart, M., Lantuejoul, S., Fievet, F., Moro, D., Sturm, N., Brambilla, C., and Brambilla, E. (2003). Value of immunohistochemical markers in preinvasive bronchial lesions in risk assessment of lung cancer. Clin Cancer Res 9, 2195-2203.
Jiang, Y., Wang, L., Gong, W., Wei, D., Le, X., Yao, J., Ajani, J., Abbruzzese, J. L., Huang, S., and Xie, K. (2004a). A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin Exp Metastasis 21, 755-764.
Jin, D., Zhang, Y., and Chen, X. (2011). Lipocalin 2 deficiency inhibits cell proliferation, autophagy, and mitochondrial biogenesis in mouse embryonic cells. Mol Cell Biochem 351, 165-172.
Jin, X., Wang, Z., Qiu, L., Zhang, D., Guo, Z., Gao, Z., Deng, C., Wang, F., Wang, S., and Guo, C. (2008). Potential biomarkers involving IKK/RelA signal in early stage non-small cell lung cancer. Cancer Sci 99, 582-589.
Johnson, L., Mercer, K., Greenbaum, D., Bronson, R. T., Crowley, D., Tuveson, D. A., and Jacks, T. (2001). Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111-1116.
Jutooru, I., Chadalapaka, G., Sreevalsan, S., Lei, P., Barhoumi, R., Burghardt, R., and Safe, S. (2010). Arsenic trioxide downregulates specificity protein (Sp) transcription factors and inhibits bladder cancer cell and tumor growth. Exp Cell Res 316, 2174-2188.
Kadonaga, J. T., Carner, K. R., Masiarz, F. R., and Tjian, R. (1987). Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 51, 1079-1090.
Karin, M., and Greten, F. R. (2005). NF-kappaB: linking inflammation and immunity to cancer development and progression. Nat Rev Immunol 5, 749-759.
Keating, A. K., Kim, G. K., Jones, A. E., Donson, A. M., Ware, K., Mulcahy, J. M., Salzberg, D. B., Foreman, N. K., Liang, X., Thorburn, A., and Graham, D. K. (2010). Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity. Mol Cancer Ther 9, 1298-1307.
Kerr, K. M. (2001). Pulmonary preinvasive neoplasia. J Clin Pathol 54, 257-271.
Khau, T., Langenbach, S. Y., Schuliga, M., Harris, T., Johnstone, C. N., Anderson, R. L., and Stewart, A. G. (2011). Annexin-1 signals mitogen-stimulated breast tumor cell proliferation by activation of the formyl peptide receptors (FPRs) 1 and 2. FASEB J 25, 483-496.
Kitamura, H., Kameda, Y., Ito, T., and Hayashi, H. (1999). Atypical adenomatous hyperplasia of the lung. Implications for the pathogenesis of peripheral lung adenocarcinoma. Am J Clin Pathol 111, 610-622.
Kitamura, H., Kameda, Y., Nakamura, N., Inayama, Y., Nakatani, Y., Shibagaki, T., Ito, T., Hayashi, H., Kimura, H., and Kanisawa, M. (1996). Atypical adenomatous hyperplasia and bronchoalveolar lung carcinoma. Analysis by morphometry and the expressions of p53 and carcinoembryonic antigen. Am J Surg Pathol 20, 553-562.
Koga, T., Hashimoto, S., Sugio, K., Yonemitsu, Y., Nakashima, Y., Yoshino, I., Matsuo, Y., Mojtahedzadeh, S., Sugimachi, K., and Sueishi, K. (2002). Lung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia. Am J Clin Pathol 117, 464-470.
Kohmo, S., Kijima, T., Otani, Y., Mori, M., Minami, T., Takahashi, R., Nagatomo, I., Takeda, Y., Kida, H., Goya, S., et al. (2010). Cell surface tetraspanin CD9 mediates chemoresistance in small cell lung cancer. Cancer Res 70, 8025-8035.
Koller, C. A., Campbell, V. W., Polansky, D. A., Mulhern, A., and Miller, D. M. (1985). In vivo differentiation of blast-phase chronic granulocytic leukemia. Expression of c-myc and c-abl protooncogenes. J Clin Invest 76, 365-369.
Koller, F. L., Hwang, D. G., Dozier, E. A., and Fingleton, B. (2010). Epithelial interleukin-4 receptor expression promotes colon tumor growth. Carcinogenesis 31, 1010-1017.
Kong, L. M., Liao, C. G., Fei, F., Guo, X., Xing, J. L., and Chen, Z. N. (2010). Transcription factor Sp1 regulates expression of cancer-associated molecule CD147 in human lung cancer. Cancer Sci 101, 1463-1470.
Kumar, A. P., and Butler, A. P. (1999). Enhanced Sp1 DNA-binding activity in murine keratinocyte cell lines and epidermal tumors. Cancer lett 137, 159-165.
Kuwahara, I., Lillehoj, E. P., Hisatsune, A., Lu, W., Isohama, Y., Miyata, T., and Kim, K. C. (2005). Neutrophil elastase stimulates MUC1 gene expression through increased Sp1 binding to the MUC1 promoter. Am J Physiol Lung Cell Mol Physiol 289, L355-362.
Kwak, H. J., Park, M. J., Cho, H., Park, C. M., Moon, S. I., Lee, H. C., Park, I. C., Kim, M. S., Rhee, C. H., and Hong, S. I. (2006). Transforming growth factor-beta1 induces tissue inhibitor of metalloproteinase-1 expression via activation of extracellular signal-regulated kinase and Sp1 in human fibrosarcoma cells. Mol Cancer Res 4, 209-220.
Lafontaine, L., Chaudhry, P., Lafleur, M. J., Van Themsche, C., Soares, M. J., and Asselin, E. (2011). Transforming growth factor Beta regulates proliferation and invasion of rat placental cell lines. Biol Reprod 84, 553-559.
Laneve, P., Di Marcotullio, L., Gioia, U., Fiori, M. E., Ferretti, E., Gulino, A., Bozzoni, I., and Caffarelli, E. (2007). The interplay between microRNAs and the neurotrophin receptor tropomyosin-related kinase C controls proliferation of human neuroblastoma cells. Proc Natl Acad Sci U S A 104, 7957-7962.
Lantuejoul, S., Salameire, D., Salon, C., and Brambilla, E. (2009). Pulmonary preneoplasia--sequential molecular carcinogenetic events. Histopathology 54, 43-54.
Lazer, G., Idelchuk, Y., Schapira, V., Pikarsky, E., and Katzav, S. (2009). The haematopoietic specific signal transducer Vav1 is aberrantly expressed in lung cancer and plays a role in tumourigenesis. J Pathol 219, 25-34.
Lee, J. A., Suh, D. C., Kang, J. E., Kim, M. H., Park, H., Lee, M. N., Kim, J. M., Jeon, B. N., Roh, H. E., Yu, M. Y., et al. (2005). Transcriptional activity of Sp1 is regulated by molecular interactions between the zinc finger DNA binding domain and the inhibitory domain with corepressors, and this interaction is modulated by MEK. J Biol Chem 280, 28061-28071.
Lee, Y. C., Oslund, K. L., Thai, P., Velichko, S., Fujisawa, T., Duong, T., Denison, M. S., and Wu, R. (2011). 2,3,7,8-Tetrachlorodibenzo-p-dioxin-induced MUC5AC expression: aryl hydrocarbon receptor-independent/EGFR/ERK/p38-dependent SP1-based transcription. Am J Respir Cell Mol Biol 45, 270-276.
Lemaitre, G., Sivan, V., Lamartine, J., Cosset, J. M., Cavelier-Balloy, B., Salomon, D., Waksman, G., and Martin, M. T. (2006). Connexin 30, a new marker of hyperproliferative epidermis. Br J Dermatol 155, 844-846.
Leroy, I., Laurent, G., and Quillet-Mary, A. (2006). Mithramycin A activates Fas death pathway in leukemic cell lines. Apoptosis 11, 113-119.
Li, S. H., Cheng, A. L., Zhou, H., Lam, S., Rao, M., Li, H., and Li, X. J. (2002). Interaction of Huntington disease protein with transcriptional activator Sp1. Mol Cell Biol 22, 1277-1287.
Li, Y., Ishiyama, S., Matsueda, S., Tsuda, N., and Ioannides, C. G. (2008). HER-2 peptides p776 and F7, N-terminal-linked with Ii-Key tetramer (LRMK) help the proliferation of E75-TCR+ cells: The dependency of help on the side chains of LRMK-extended peptide pointed towards the T cell receptor. Oncol Rep 19, 1445-1452.
Liao, D., Corle, C., Seagroves, T. N., and Johnson, R. S. (2007). Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res 67, 563-572.
Lietard, J., Musso, O., Theret, N., L'Helgoualc'h, A., Campion, J. P., Yamada, Y., and Clement, B. (1997). Sp1-mediated transactivation of LamC1 promoter and coordinated expression of laminin-gamma1 and Sp1 in human hepatocellular carcinomas. Am J Pathol 151, 1663-1672.
Lin, R. K., Hsu, C. H., and Wang, Y. C. (2007). Mithramycin A inhibits DNA methyltransferase and metastasis potential of lung cancer cells. Anticancer Drugs 18, 1157-1164.
Lin, R. K., Wu, C. Y., Chang, J. W., Juan, L. J., Hsu, H. S., Chen, C. Y., Lu, Y. Y., Tang, Y. A., Yang, Y. C., Yang, P. C., and Wang, Y. C. (2010). Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res 70, 5807-5817.
Liu, H., Ma, Q., and Li, J. (2011). High glucose promotes cell proliferation and enhances GDNF and RET expression in pancreatic cancer cells. Mol Cell Biochem 347, 95-101.
Liu, Y. N., Lee, W. W., Wang, C. Y., Chao, T. H., Chen, Y., and Chen, J. H. (2005). Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 24, 8277-8290.
Lockwood, W. W., Chari, R., Coe, B. P., Girard, L., Macaulay, C., Lam, S., Gazdar, A. F., Minna, J. D., and Lam, W. L. (2008). DNA amplification is a ubiquitous mechanism of oncogene activation in lung and other cancers. Oncogene 27, 4615-4624.
Logotheti, S., Michalopoulos, I., Sideridou, M., Daskalos, A., Kossida, S., Spandidos, D. A., Field, J. K., Vojtesek, B., Liloglou, T., Gorgoulis, V., and Zoumpourlis, V. (2010). Sp1 binds to the external promoter of the p73 gene and induces the expression of TAp73gamma in lung cancer. The FEBS journal 277, 3014-3027.
Lou, Z., O'Reilly, S., Liang, H., Maher, V. M., Sleight, S. D., and McCormick, J. J. (2005). Down-regulation of overexpressed sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. Cancer Res 65, 1007-1017.
Ma, S. H., Chen, G. G., Yip, J., and Lai, P. B. (2010). Therapeutic effect of alpha-fetoprotein promoter-mediated tBid and chemotherapeutic agents on orthotopic liver tumor in mice. Gene Ther 17, 905-912.
Ma, Y., Lin, D., Sun, W., Xiao, T., Yuan, J., Han, N., Guo, S., Feng, X., Su, K., Mao, Y., et al. (2006). Expression of targeting protein for xklp2 associated with both malignant transformation of respiratory epithelium and progression of squamous cell lung cancer. Clin Cancer Res 12, 1121-1127.
Maeda, Y., Dave, V., and Whitsett, J. A. (2007). Transcriptional control of lung morphogenesis. Physiol Rev 87, 219-244.
Mann, V., Hobson, E. E., Li, B., Stewart, T. L., Grant, S. F., Robins, S. P., Aspden, R. M., and Ralston, S. H. (2001). A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality. J Clin Investi 107, 899-907.
Maor, S., Mayer, D., Yarden, R. I., Lee, A. V., Sarfstein, R., Werner, H., and Papa, M. Z. (2006). Estrogen receptor regulates insulin-like growth factor-I receptor gene expression in breast tumor cells: involvement of transcription factor Sp1. J Endocrinol 191, 605-612.
Marconett, C. N., Sundar, S. N., Tseng, M., Tin, A. S., Tran, K. Q., Mahuron, K. M., Bjeldanes, L. F., and Firestone, G. L. (2011). Indole-3-carbinol downregulation of telomerase gene expression requires the inhibition of estrogen receptor-alpha and Sp1 transcription factor interactions within the hTERT promoter and mediates the G1 cell cycle arrest of human breast cancer cells. Carcinogenesis 32, 1315-1323.
McCarty, K. S., Jr., Miller, L. S., Cox, E. B., Konrath, J., and McCarty, K. S., Sr. (1985). Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies. Arch Pathol Lab Med 109, 716-721.
Milanini-Mongiat, J., Pouyssegur, J., and Pages, G. (2002). Identification of two Sp1 phosphorylation sites for p42/p44 mitogen-activated protein kinases: their implication in vascular endothelial growth factor gene transcription. J Biol Chem 277, 20631-20639.
Milatovich, A., Kitamura, T., Miyajima, A., and Francke, U. (1993). Gene for the alpha-subunit of the human interleukin-3 receptor (IL3RA) localized to the X-Y pseudoautosomal region. Am J Hum Genet 53, 1146-1153.
Miller, D. M., Polansky, D. A., Thomas, S. D., Ray, R., Campbell, V. W., Sanchez, J., and Koller, C. A. (1987). Mithramycin selectively inhibits transcription of G-C containing DNA. Am J Med Sci 294, 388-394.
Mitchell, D. C., Stafford, L. J., Li, D., Bar-Eli, M., and Liu, M. (2007). Transcriptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein-1 and its coactivator DRIP-130. Oncogene 26, 1739-1747.
Moreb, J. S., Baker, H. V., Chang, L. J., Amaya, M., Lopez, M. C., Ostmark, B., and Chou, W. (2008). ALDH isozymes downregulation affects cell growth, cell motility and gene expression in lung cancer cells. Mol Cancer 7, 87.
Morin, P. J., Sparks, A. B., Korinek, V., Barker, N., Clevers, H., Vogelstein, B., and Kinzler, K. W. (1997). Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275, 1787-1790.
Mullauer, F. B., Kessler, J. H., and Medema, J. P. (2010). Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs 21, 215-227.
Naoki, K., Chen, T. H., Richards, W. G., Sugarbaker, D. J., and Meyerson, M. (2002). Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 62, 7001-7003.
Nesmelova, I. V., Sham, Y., Gao, J., and Mayo, K. H. (2008). CXC and CC chemokines form mixed heterodimers: association free energies from molecular dynamics simulations and experimental correlations. J Biol Chem 283, 24155-24166.
Ness, S. L., Edelmann, W., Jenkins, T. D., Liedtke, W., Rustgi, A. K., and Kucherlapati, R. (1998). Mouse keratin 4 is necessary for internal epithelial integrity. J Biol Chem 273, 23904-23911.
Nicolas, M., Noe, V., Jensen, K. B., and Ciudad, C. J. (2001). Cloning and characterization of the 5'-flanking region of the human transcription factor Sp1 gene. J Biol Chem 276, 22126-22132.
Olivier, M., Petitjean, A., Marcel, V., Petre, A., Mounawar, M., Plymoth, A., de Fromentel, C. C., and Hainaut, P. (2009). Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther 16, 1-12.
Pao, W., Wang, T. Y., Riely, G. J., Miller, V. A., Pan, Q., Ladanyi, M., Zakowski, M. F., Heelan, R. T., Kris, M. G., and Varmus, H. E. (2005). KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2, e17.
Peng, X. D., Xu, P. Z., Chen, M. L., Hahn-Windgassen, A., Skeen, J., Jacobs, J., Sundararajan, D., Chen, W. S., Crawford, S. E., Coleman, K. G., and Hay, N. (2003). Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2. Genes Dev 17, 1352-1365.
Pisha, E., Chai, H., Lee, I. S., Chagwedera, T. E., Farnsworth, N. R., Cordell, G. A., Beecher, C. W., Fong, H. H., Kinghorn, A. D., Brown, D. M., and et al. (1995). Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat Med 1, 1046-1051.
Qu, P., Du, H., Wilkes, D. S., and Yan, C. (2009). Critical roles of lysosomal acid lipase in T cell development and function. Am J Pathol 174, 944-956.
Remsing, L. L., Bahadori, H. R., Carbone, G. M., McGuffie, E. M., Catapano, C. V., and Rohr, J. (2003). Inhibition of c-src transcription by mithramycin: structure-activity relationships of biosynthetically produced mithramycin analogues using the c-src promoter as target. Biochemistry 42, 8313-8324.
Rivard, N. (2009). Phosphatidylinositol 3-kinase: a key regulator in adherens junction formation and function. Front Biosci 14, 510-522.
Roos, M. D., Su, K., Baker, J. R., and Kudlow, J. E. (1997). O glycosylation of an Sp1-derived peptide blocks known Sp1 protein interactions. Mol Cell Biol 17, 6472-6480.
Roose, J., Huls, G., van Beest, M., Moerer, P., van der Horn, K., Goldschmeding, R., Logtenberg, T., and Clevers, H. (1999). Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1. Science 285, 1923-1926.
Rossner, S., Sastre, M., Bourne, K., and Lichtenthaler, S. F. (2006). Transcriptional and translational regulation of BACE1 expression--implications for Alzheimer's disease. Prog Neurobiol 79, 95-111.
Rotondo, R., Barisione, G., Mastracci, L., Grossi, F., Orengo, A. M., Costa, R., Truini, M., Fabbi, M., Ferrini, S., and Barbieri, O. (2009). IL-8 induces exocytosis of arginase 1 by neutrophil polymorphonuclears in nonsmall cell lung cancer. Int J Cancer 125, 887-893.
Rovina, N., Hillas, G., Dima, E., Vlastos, F., Loukides, S., Veldekis, D., Roussos, C., Alhanatis, M., and Bakakos, P. (2011). VEGF and IL-18 in induced sputum of lung cancer patients. Cytokine 54, 277-281.
Salaun, B., de Saint-Vis, B., Pacheco, N., Pacheco, Y., Riesler, A., Isaac, S., Leroux, C., Clair-Moninot, V., Pin, J. J., Griffith, J., et al. (2004). CD208/dendritic cell-lysosomal associated membrane protein is a marker of normal and transformed type II pneumocytes. Am J Pathol 164, 861-871.
Saluja, D., Vassallo, M. F., and Tanese, N. (1998). Distinct subdomains of human TAFII130 are required for interactions with glutamine-rich transcriptional activators. Mol Cell Biol 18, 5734-5743.
Sanchez, A. P., and Sharma, K. (2009). Transcription factors in the pathogenesis of diabetic nephropathy. Expert Rev Mol Med 11, e13.
Sawada, N., Kataoka, K., Kondo, K., Arimochi, H., Fujino, H., Takahashi, Y., Miyoshi, T., Kuwahara, T., Monden, Y., and Ohnishi, Y. (2004). Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. Br J Cancer 90, 1672-1678.
Schmalhofer, O., Brabletz, S., and Brabletz, T. (2009). E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev 28, 151-166.
Schmidt, N. W., Mayo, L. D., Donner, D. B., and Kaplan, M. H. (2006). p53 regulates Btk-dependent B cell proliferation but not differentiation. J Leukoc Biol 79, 852-859.
Sevenich, L., Schurigt, U., Sachse, K., Gajda, M., Werner, F., Muller, S., Vasiljeva, O., Schwinde, A., Klemm, N., Deussing, J., et al. (2010). Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice. Proc Natl Acad Sci U S A 107, 2497-2502.
Shahrabani-Gargir, L., Pandita, T. K., and Werner, H. (2004). Ataxia-telangiectasia mutated gene controls insulin-like growth factor I receptor gene expression in a deoxyribonucleic acid damage response pathway via mechanisms involving zinc-finger transcription factors Sp1 and WT1. Endocrinology 145, 5679-5687.
Shan, L., Emanuel, R. L., Dewald, D., Torday, J. S., Asokanathan, N., Wada, K., Wada, E., and Sunday, M. E. (2004). Bombesin-like peptide receptor gene expression, regulation, and function in fetal murine lung. Am J Physiol Lung Cell Mol Physiol 286, L165-173.
Shi, Q., Le, X., Abbruzzese, J. L., Peng, Z., Qian, C. N., Tang, H., Xiong, Q., Wang, B., Li, X. C., and Xie, K. (2001). Constitutive Sp1 activity is essential for differential constitutive expression of vascular endothelial growth factor in human pancreatic adenocarcinoma. Cancer Res 61, 4143-4154.
Shimada, A., Kano, J., Ishiyama, T., Okubo, C., Iijima, T., Morishita, Y., Minami, Y., Inadome, Y., Shu, Y., Sugita, S., et al. (2005). Establishment of an immortalized cell line from a precancerous lesion of lung adenocarcinoma, and genes highly expressed in the early stages of lung adenocarcinoma development. Cancer Sci 96, 668-675.
Soltermann, A., Tischler, V., Arbogast, S., Braun, J., Probst-Hensch, N., Weder, W., Moch, H., and Kristiansen, G. (2008). Prognostic significance of epithelial-mesenchymal and mesenchymal-epithelial transition protein expression in non-small cell lung cancer. Clin Cancer Res 14, 7430-7437.
St Clair, S., and Manfredi, J. J. (2006). The dual specificity phosphatase Cdc25C is a direct target for transcriptional repression by the tumor suppressor p53. Cell Cycle 5, 709-713.
Su, K., Roos, M. D., Yang, X., Han, I., Paterson, A. J., and Kudlow, J. E. (1999). An N-terminal region of Sp1 targets its proteasome-dependent degradation in vitro. J Biol Chem 274, 15194-15202.
Sun, X., Ritzenthaler, J. D., Zhong, X., Zheng, Y., Roman, J., and Han, S. (2009). Nicotine stimulates PPARbeta/delta expression in human lung carcinoma cells through activation of PI3K/mTOR and suppression of AP-2alpha. Cancer Res 69, 6445-6453.
Sung, H. J., and Cho, J. Y. (2008). Biomarkers for the lung cancer diagnosis and their advances in proteomics. BMB reports 41, 615-625.
Suske, G., Bruford, E., and Philipsen, S. (2005). Mammalian SP/KLF transcription factors: bring in the family. Genomics 85, 551-556.
Swinson, D. E., Jones, J. L., Richardson, D., Wykoff, C., Turley, H., Pastorek, J., Taub, N., Harris, A. L., and O'Byrne, K. J. (2003). Carbonic anhydrase IX expression, a novel surrogate marker of tumor hypoxia, is associated with a poor prognosis in non-small-cell lung cancer. J Clin Oncol 21, 473-482.
Tanaka, H., Yanagisawa, K., Shinjo, K., Taguchi, A., Maeno, K., Tomida, S., Shimada, Y., Osada, H., Kosaka, T., Matsubara, H., et al. (2007). Lineage-specific dependency of lung adenocarcinomas on the lung development regulator TTF-1. Cancer Res 67, 6007-6011.
Tanese, N., Saluja, D., Vassallo, M. F., Chen, J. L., and Admon, A. (1996). Molecular cloning and analysis of two subunits of the human TFIID complex: hTAFII130 and hTAFII100. Proc Natl Acad Sci U S A 93, 13611-13616.
Tang, C. K., Concepcion, X. Z., Milan, M., Gong, X., Montgomery, E., and Lippman, M. E. (1999). Ribozyme-mediated down-regulation of ErbB-4 in estrogen receptor-positive breast cancer cells inhibits proliferation both in vitro and in vivo. Cancer Res 59, 5315-5322.
Tangye, S. G., van de Weerdt, B. C., Avery, D. T., and Hodgkin, P. D. (2002). CD84 is up-regulated on a major population of human memory B cells and recruits the SH2 domain containing proteins SAP and EAT-2. Eur J Immunol 32, 1640-1649.
Thiery, J. P. (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2, 442-454.
Thurnher, D., Turhani, D., Pelzmann, M., Wannemacher, B., Knerer, B., Formanek, M., Wacheck, V., and Selzer, E. (2003). Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. Head Neck 25, 732-740.
Tian, H., Qian, G. W., Li, W., Chen, F. F., Di, J. H., Zhang, B. F., Pei, D. S., Ma, P., and Zheng, J. N. (2011). A critical role of Sp1 transcription factor in regulating the human Ki-67 gene expression. Tumour Biol 32, 273-283.
Todaro, M., Lombardo, Y., Francipane, M. G., Alea, M. P., Cammareri, P., Iovino, F., Di Stefano, A. B., Di Bernardo, C., Agrusa, A., Condorelli, G., et al. (2008). Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. Cell Death Differ 15, 762-772.
Tomihari, M., Chung, J. S., Akiyoshi, H., Cruz, P. D., Jr., and Ariizumi, K. (2010). DC-HIL/glycoprotein Nmb promotes growth of melanoma in mice by inhibiting the activation of tumor-reactive T cells. Cancer Res 70, 5778-5787.
Tsai, M. F., Wang, C. C., Chang, G. C., Chen, C. Y., Chen, H. Y., Cheng, C. L., Yang, Y. P., Wu, C. Y., Shih, F. Y., Liu, C. C., et al. (2006). A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst 98, 825-838.
Ucar, D., Cogle, C. R., Zucali, J. R., Ostmark, B., Scott, E. W., Zori, R., Gray, B. A., and Moreb, J. S. (2009). Aldehyde dehydrogenase activity as a functional marker for lung cancer. Chem Biol Interact 178, 48-55.
Ueno, H., Murphy, J., Jass, J. R., Mochizuki, H., and Talbot, I. C. (2002). Tumour 'budding' as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 40, 127-132.
Ushizawa, K., Takahashi, T., Hosoe, M., Kizaki, K., and Hashizume, K. (2010). Cleaved bovine prolactin-related protein-I stimulates vascular endothelial cell proliferation. Mol Cell Endocrinol 323, 277-281.
Van Dyke, M. W., and Dervan, P. B. (1983). Chromomycin, mithramycin, and olivomycin binding sites on heterogeneous deoxyribonucleic acid. Footprinting with (methidiumpropyl-EDTA)iron(II). Biochemistry 22, 2373-2377.
Wang, L., Wei, D., Huang, S., Peng, Z., Le, X., Wu, T. T., Yao, J., Ajani, J., and Xie, K. (2003). Transcription factor Sp1 expression is a significant predictor of survival in human gastric cancer. Clin Cancer Res 9, 6371-6380.
Wang, X., Chen, W., and Lin, Y. (2007). Sensitization of TNF-induced cytotoxicity in lung cancer cells by concurrent suppression of the NF-kappaB and Akt pathways. Biochem Biophys Res Commun 355, 807-812.
Wang, X., Dai, S., Zhang, Z., Liu, L., Wang, J., Xiao, X., He, D., and Liu, B. (2009). Characterization of apolipoprotein A-I as a potential biomarker for cholangiocarcinoma. Eur J Cancer Care (Engl) 18, 625-635.
Wang, Y. T., Chuang, J. Y., Shen, M. R., Yang, W. B., Chang, W. C., and Hung, J. J. (2008b). Sumoylation of specificity protein 1 augments its degradation by changing the localization and increasing the specificity protein 1 proteolytic process. J Mol Biol 380, 869-885.
Wei, D., Wang, L., He, Y., Xiong, H. Q., Abbruzzese, J. L., and Xie, K. (2004). Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res 64, 2030-2038.
Wierstra, I. (2008). Sp1: emerging roles--beyond constitutive activation of TATA-less housekeeping genes. Biochem Biophys Res Commun 372, 1-13.
Wistuba, II, and Gazdar, A. F. (2006). Lung cancer preneoplasia. Annu Rev Pathol 1, 331-348.
Wood, L. D., Calhoun, E. S., Silliman, N., Ptak, J., Szabo, S., Powell, S. M., Riggins, G. J., Wang, T. L., Yan, H., Gazdar, A., et al. (2006). Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human cancers. Hum Mutat 27, 1060-1061.
Yamamoto, H., Shigematsu, H., Nomura, M., Lockwood, W. W., Sato, M., Okumura, N., Soh, J., Suzuki, M., Wistuba, II, Fong, K. M., et al. (2008). PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 68, 6913-6921.
Yang, T. P., Chiou, H. L., Maa, M. C., and Wang, C. J. (2010). Mithramycin inhibits human epithelial carcinoma cell proliferation and migration involving downregulation of Eps8 expression. Chem Biol Interact 183, 181-186.
Yang, X., Su, K., Roos, M. D., Chang, Q., Paterson, A. J., and Kudlow, J. E. (2001). O-linkage of N-acetylglucosamine to Sp1 activation domain inhibits its transcriptional capability. Proc Natl Acad Sci U S A 98, 6611-6616.
Yao, J. C., Wang, L. W., Wei, D. Y., Gong, W. D., Hassan, M., Wu, T. T., Mansfield, P., Ajani, J., and Xie, K. P. (2004b). Association between expression of transcription factor Sp1 and increased vascular endothelial growth factor expression, advanced stage, and poor survival in patients with resected gastric cancer. Clinical Cancer Research 10, 4109-4117.
Yasmeen, A., Berdel, W. E., Serve, H., and Muller-Tidow, C. (2003). E- and A-type cyclins as markers for cancer diagnosis and prognosis. Expert Rev Mol Diagn 3, 617-633.
Yatabe, Y., Kosaka, T., Takahashi, T., and Mitsudomi, T. (2005). EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol 29, 633-639.
Yatabe, Y., Mitsudomi, T., and Takahashi, T. (2002). TTF-1 expression in pulmonary adenocarcinomas. Am J Surg Pathol 26, 767-773.
Yi, T., Tan, K., Cho, S. G., Wang, Y., Luo, J., Zhang, W., Li, D., and Liu, M. (2010). Regulation of embryonic kidney branching morphogenesis and glomerular development by KISS1 receptor (Gpr54) through NFAT2- and Sp1-mediated Bmp7 expression. J Biol Chem 285, 17811-17820.
Yuan, P., Wang, L., Wei, D., Zhang, J., Jia, Z., Li, Q., Le, X., Wang, H., Yao, J., and Xie, K. (2007). Therapeutic inhibition of Sp1 expression in growing tumors by mithramycin a correlates directly with potent antiangiogenic effects on human pancreatic cancer. Cancer 110, 2682-2690.
Zhai, W., Jeong, H., Cui, L., Krainc, D., and Tjian, R. (2005). In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets. Cell 123, 1241-1253.
Zhang, F. L., Kirschmeier, P., Carr, D., James, L., Bond, R. W., Wang, L., Patton, R., Windsor, W. T., Syto, R., Zhang, R. M., and Bishop, W. R. (1997). Characterization of Ha-Ras, N-Ras, Ki-Ras4A, and Ki-Ras4B as in vitro substrates for farnesyl protein transferase and geranylgeranyl protein transferase type I. J Biol Chem 272, 10232-10239.
Zhang, J. X., Ma, H. W., Sang, M., Hu, Y. S., Liang, Z. N., Ai, H. X., Zhang, J., Cui, X. W., and Zhang, S. Q. (2010). Molecular structure, expression, cell and tissue distribution, immune evolution and cell proliferation of the gene encoding bovine (Bos taurus) TNFSF13 (APRIL). Dev Comp Immunol 34, 1199-1208.
Zhang, R., Wu, Y., Zhao, M., Liu, C., Zhou, L., Shen, S., Liao, S., Yang, K., Li, Q., and Wan, H. (2009). Role of HIF-1alpha in the regulation ACE and ACE2 expression in hypoxic human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 297, L631-640.
Zheng, Y., Ritzenthaler, J. D., Sun, X., Roman, J., and Han, S. (2009). Prostaglandin E2 stimulates human lung carcinoma cell growth through induction of integrin-linked kinase: the involvement of EP4 and Sp1. Cancer Res 69, 896-904.
Zhong, L., Roybal, J., Chaerkady, R., Zhang, W., Choi, K., Alvarez, C. A., Tran, H., Creighton, C. J., Yan, S., Strieter, R. M., et al. (2008). Identification of secreted proteins that mediate cell-cell interactions in an in vitro model of the lung cancer microenvironment. Cancer Res 68, 7237-7245.
Zuco, V., Supino, R., Righetti, S. C., Cleris, L., Marchesi, E., Gambacorti-Passerini, C., and Formelli, F. (2002). Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer lett 175, 17-25.