1.p53是一個抑癌基因，它對於不正常細胞中的控制生長、存活和運動性都扮演了一個相當重要的角色。一般來說，p53在正常細胞中的表現量是相當少的。cisplatin為一種廣泛被使用之肺癌治療的基底藥，它會對細胞造成毒性刺激細胞引發細胞產生大量的細胞凋亡現象。利用流式細胞分析，當p53在肺癌A549細胞中經由RNA干擾掉後，其細胞週期中的S時期會變多，表示生長速度變快；但把點突變的p53基因送入正常A549細胞表現 (H179Y/A549 cells)時，S時期細胞的數目很明顯的下降也就是生長速率被抑制了。由於p53被抑制使得p21的表現量也因此被抑制，造成p21無法表現而使細胞無法產生G1 停滯的現象。p53 RNAi/A549 細胞中在Bax和COX-2表現量比較低且對cisplatin的影響更敏感，Bax的蛋白量會有增加的趨勢且procaspase-3有減少，細胞可能經由Bax活化導致細胞凋亡，而COX-2的蛋白量會被抑制，表示可能有抑制抗細胞凋亡的現象產生。利用MTS assay、計數細胞實驗和流式細胞分析，在不同時間點觀察，細胞缺乏p53對cisplatin的影響比較敏感，其存活率相較於正常A549細胞是明顯降低的，且在H1355細胞中也有相類似的結果。相反的，比較細胞計數實驗、細胞週期和細胞存活率的結果，發現在不同濃度之cisplatin處理細胞下，缺乏p53細胞中所生成的群落反而是比較多的，這顯示cisplatin對p53 RNAi/A549的細胞毒性是比較強的。利用wound healing assay測量細胞的移動性發現到過量表現突變型 (H179Y/A549)細胞移動最明顯，pcDNA/A549細胞次之，而p53 RNAi/A549細胞最少。並進一步證明出由於MMP-2活性受到改變的關係。我們利用二維電泳也觀察到A549細胞中有不同蛋白受到p53調控而改變的，在未來將再進一步確定這些蛋白為何。
2.松杉靈芝免疫調節蛋白 (FIP-gts)是先前由松杉靈芝(Ganoderma tsugae)當中發現的真菌類免疫調節蛋白。有研究指出此蛋白可以促使HPBMCs (Human peripheral blood mononuclear cells)的細胞週期由G0/G1期進入S期進而造成細胞增生。但是FIP-gts對於癌症細胞的作用並沒有很清楚的被研究和探討。以colony formation的分析方式偵測FIP-gts對細胞毒性時，具有毒殺肺癌細胞株的能力，且利用MTS方法或是細胞計數實驗中皆對A549及H1355肺癌細胞其細胞存活率造成下降的趨勢。接著更發現FIP-gts會促進A549細胞在G1期有停滯的現象，也因此造成S期的下降，換句話說，細胞的增生因此被抑制，進而導致細胞的存活率下降，也發現A549細胞之p53會被活化，進一步導致其下游基因p21表現出來，這可能就是造成A549細胞G1期停滯的原因。FIP-gts對肺癌細胞的的凋亡情形以流式細胞分析儀分析在subG1只有些許的增加且同時可以觀察到procaspase 3的蛋白量也有些微降低，使caspase 3活化因而導致細胞的細胞凋亡現象。但是有抗細胞凋亡的蛋白COX-2卻同時有被誘導出來的現象，所以FIP-gts促進肺癌細胞凋亡的能力非常弱。當FIP-gts處理A549細胞中都能很明顯的造成細胞的形狀變成圓形的，但在正常肺細胞BEAS-2B中卻沒看到明顯的形態變化。利用受傷癒合分析 (wound healing assay)發現在加入較高濃度的FIP-gts相對的也增強了抑制細胞移動性。而用gelatin-zymography方式偵測MMP (Matrix metalloproteinases)活性，FIP-gts會抑制MMP-2的活性，且利用RT-PCR的方式觀察MMP的抑制劑TIMP-1和TIMP-2，TIMP-1則受到FIP-gts增加其表現，但TIMP-2則沒有變化，而MMP-2的量同時也看到有發生變化，因而抑制MMP的活性，使得細胞移動性也被抑制，同時也看到而PA的抑制劑PAI也有受到活化。所以本研究闡示松杉靈芝免疫調節蛋白 (FIP-gts)抗癌作用不只毒殺肺癌細胞更有潛力發展抑制細胞轉移能力。

1. p53 is a tumor suppressor gene, which plays a central role in the native control of growth, survival and migration of abnormal cells. The protein level of p53 in normal cells is extremely low. The aim of the study was invastigate the complex consequences on the cellular responses of RNA interference of p53 in A549 cells to anticancer drug, cisplatin. When p53 expression was inhibited by RNA interference in an adenocarcinoma cell line A549 (p53 RNAi/A549 cells), cells exhibited a faster growth rate as a greater percentage of cells in S phase than A549 cells with wild type p53 (pcDNA/A549 cells). But, point mutation p53 overexpression in A549 cells (H179Y/A549 cells) reduced growth rate as a lower percentage of cells in S phase than pcDNA/A549 cells by flow cytometry assay. However, the effect of cisplatin to cells depleting of p53 reduced p21 expression that caused to G1 arrest. Bax and COX-2 had less expression and more sensitive in p53 RNAi/A549 cells after treated with cisplatin. Cells lacking of p53 were also more sensitive to cisplatin treatment by MTS assay, counting cell numbers and flow cytometry measuring after different days. In contrast to cell cycle and cell mortality analysis, p53 RNAi/A549 cells had a better colony formation ability after cisplatin treatment. It was suggest that cisplatin had more cytotoxicity to pcDNA/A549 cells than p53 RNAi/A549 cells. In wound migration assay, the motility of p53 RNAi/A549 cells was lower than pcDNA/A549 cells but H179Y/A549 cells had a highest motility. It was due to the changes in MMP-2 activity secreted by A549 cells. We also observed different proteins that changed between p53 RNAi/A549 cells and pcDNA/A549 cells using 2-DE gel analysis. We are going to identify these proteins in the future.
2.Fungal immunomodulatory proteins, FIP-gts, were found in Ganoderma tsugae. The protein has been implicated which activates human peripheral blood mononuclear cells. However, the effect of FIP-gts in cancer cells has not clearly been described. Metastasis was one of the most difficult problems in lung cancer therapy. We observed the A549 cells turn into round shape and were not changed cell shapes in normal cell line-BEAS-2B after FIP-gts treatment. MTS anlysis and counting cell numbers decreased the viability of A549 cells. In colony formation assay, FIP-gts showed cytotoxicity to A549 cells. FIP-gts induced p53 expression that in terms induced p21 activity, which caused in G1 arrest. In addition, procaspase-3 by western blotting was decreased. Similarly, there was a small amount of subG1 increased after FIP-gts treatment. But, COX-2 that has the function of anti-apoptosis, increased after treated with FIP-gts. In wound healing assay, the level of motility were decreased by the increasing concentration of FIP-gts. MMP-2 activity was also decreased measured by gelatin-zymography. In RT-PCR, the level of MMP-2 decreased but TIMP-2 had no effect and the MMP inhibitor TIMP-1 and PA inhibitor PAI were increased after treated with FIP-gts. Alltogether, FIP-gts could not only cause cytotoxicity but also potentially inhibit metastasis.

目 錄 (Content)
頁次
Part I. 5
壹、 中文摘要 6
貳、 英文摘要 (Abstract) 7
叁、 縮寫表 (Abbreviation) 8
肆、 緒論 (Introduction) 10
一、 肺癌流行病學及危險因子 10
二、 肺癌治療與細胞凋亡 (Lung Cancer Therapy and Cell Apoptosis) 11
三、 腫瘤細胞的轉移 (Metastasis) 13
四、 Matrix metalloproteinase (MMPs) 14
(1) 基質金屬蛋白水解酵素之分類 14
(2) 基質金屬蛋白水解酵素的表現與調控 15
(3) 基質金屬蛋白水解酵素活化機制 16
五、 Cisplatin的介紹 16
六、 p53的介紹 17
七、 細胞週期(Cell cycle)調控蛋白 18
(1) G1/S checkpoint： 19
(2) S checkpoint： 19
(3) G2 checkpoint： 20
八、 RNA interference 21
(1) 起始階段（Initiation stage） 21
(2) 中繼階段（Effector stage） 22
伍、 研究動機 (Motivation) 24
陸、 實驗材料 (Materials) 25
一、 藥品試劑 (Drugs and reagent) 25
二、 實驗設備 (Instruments) 26
三、 人類肺癌細胞株 (Cell lines)之來源 27
柒、 實驗方法 (Methods) 28
一、 細胞培養 (Cell culture) 28
(1) 細胞培養 (Cell culture) 28
(2) 繼代培養 (Replate cell) 28
(3) 冷凍細胞 (Frozen cell) 28
(4) 解凍細胞 (Defrozen cell) 29
(5) DNA轉殖 (Transfection) 29
二、 細胞傷口癒合試驗 (Wound healing assay) 30
三、 細胞存活率試驗 (Cell viability assay) 30
(1) 計算細胞數目 (Counting cell numbers) 30
(2) CellTiter 96 Aqueous Non-Radioactivative Cell Proliferation Assay (MTS) 31
(3) 群落形成試驗 (Colony formation) 31
四、 流式細胞分析 (Flow cytometry) 32
五、 凝膠菜瓊脂電泳分析 (Agarose gel electrophoresis) 32
(1) 1.5 % agarose gel的製備方法 32
(2) 電泳操作 32
(3) 由Agarose gel回收DNA片段 (Elution) 33
六、 轉形作用 (Transformation) 34
(1) 勝任細胞 (Competent cells)製備 34
(2) 轉形作用的步驟 34
(3) 質體DNA的微量抽取 35
七、 西方點墨法 (Western blot) 35
(1) 樣品製備 (Sample preparing) 35
(2) 蛋白濃度定量分析 (Protein quantification) 36
(3) SDS-聚丙烯醯胺板膠電泳之轉漬 (SDS-PAGE) 36
(4) 抗體作用及偵測方法 (Antibody detection) 37
八、 酵素活性分析 (Gelatin zymogragphy) 38
九、 二維電泳法 (2-D Electrophoresis) 39
捌、結果 (Results) 40
一、 製作p53 RNAi 載體之control載體 - pcDNA/CMV-/HU6+ 40
二、 化療藥cisplatin對有p53干擾的A549細胞株的生長情形之影響 40
三、 探討經由化療藥cisplatin導致有p53干擾的A549細胞株的生長情形有差異的機制 41
四、 化療藥cisplatin對肺癌p53 RNAi/A549細胞和pcDNA/A549細胞之細胞週期影響之分析 42
五、 化療藥cisplatin對肺癌p53 RNAi/A549細胞和pcDNA/A549細胞造成之細胞毒性 43
六、 分析肺癌p53 RNAi/A549細胞和pcDNA/A549細胞之移行性 43
七、 經由流式細胞儀分析在不同細胞株中細胞週期的狀況 43
八、 觀察p53 RNAi/A549細胞和pcDNA/A549細胞蛋白表現的差異 44
玖、討論 (Discussion) 46
拾、圖表說明 (Figures and Tables) 50
Figure 1 製作pcDNA/CMV-/HU6+的載體 50
Figure 2 用MTS偵cisplatin對細胞生長的影響 51
Figure 3 用計數細胞數方法在不同時間偵測cisplatin對p53 RNAi/A549細胞和pcDNA/A549細胞的生長影響 52
Figure 4 處理cisplatin誘導p53、Bax和procaspase3的情形 53
Figure 5 處理cisplatin誘導p53、p21和COX-2的情形 54
Figure 6 處理cisplatin對p53 RNAi/A549細胞和pcDNA/A549細胞的細胞週期之影響 55
Figure 7 處理cisplatin對p53 RNAi/A549細胞和pcDNA/A549細胞在colony formation的影響 56
Figure 8 處理cisplatin對MMP-2活性的影響 57
Figure 9 在A549細胞中進行stable clone 的篩選 58
Figure 10 細胞中p53不同的表達情況的對細胞移動性的影響 59
Figure 11 細胞中p53不同的表達情況對MMP-2活性的影響 60
Figure 12 細胞中p53不同的表達情況對細胞週期的影響 61
Figure 13 p53 RNAi/A549細胞和pcDNA/A549細胞其蛋白表現量的比較 62
拾壹、參考文獻 (References) 63
Part II. 74
壹、中文摘要 75
貳、英文摘要 (Abstract) 76
叁、緒論 (Introduction) 77
一、 靈芝 77
二、 松杉靈芝免疫調節功能蛋白 (Fungal immunodulatory protein, FIP-gts) 80
三、 松杉靈芝免疫調節功能蛋白具有的生理活性 81
四、 Tissue inhibitor metalloproteinases (TIMP) 81
五、 Plasminogen activator inhibitor (PAI) 82
六、 E-cadherin 82
肆、研究動機 (Motivation) 84
伍、實驗方法 (Methods) 85
一、 反轉錄酶-聚合酶連鎖反應 (RT-PCR) 85
陸、結果 (Results) 87
一、 觀察松杉靈芝免疫調節功能蛋白對肺癌A549細胞造成之影響 87
二、 松杉靈芝免疫調節功能蛋白對肺癌A549之細胞存活率 87
三、 松杉靈芝免疫調節功能蛋白對肺癌A549造成之細胞毒性 88
四、 松杉靈芝免疫調節功能蛋白對肺癌A549細胞之細胞週期影響之分析 88
五、 松杉靈芝免疫調節功能蛋白對肺癌A549細胞週期有關之checkpoint或細胞凋亡蛋白的影響 89
六、 松杉靈芝免疫調節功能蛋白對細胞移行性 (Migration) 之影響 89
柒、討論 (Discussion) 91
捌、圖表說明 (Figures and Tables) 95
Figure 1 處理FIP-gts對A549細胞型態的影響 96
Figure 2 處理FIP-gts對BEAS-2B細胞型態的影響 96
Figure 3 用MTS偵FIP-gts對細胞生長的影響 97
Figure 4 用計數細胞數方法在不同時間偵測FIP-gts對細胞的生長影響 98
Figure 5 處理FIP-gts對A549細胞在colony formation的影響 99
Figure 6 處理FIP-gts對A549細胞的細胞週期之影響 100
Figure 7 處理cisplatin誘導p53、p21、procaspase3和COX-2的情形101
Figure 8 處理FIP-gts對細胞移動性的影響 102
Figure 9 處理FIP-gts對MMP-2活性的影響 103
Figure 10 處理FIP-gts對TIMP-1在mRNA上的影響 104
Figure 11 處理FIP-gts對MMP-2在mRNA上的影響 105
Figure 12 處理FIP-gts對TIMP-2在mRNA上的影響 106
Figure 13 處理FIP-gts對PAI在mRNA上的影響 107
Figure 14 處理FIP-gts對E-cadherin在mRNA上的影響 108
玖、參考文獻 (References) 109
拾、附圖表 118

參考文獻 ( Reference )
Abraham, R.T. (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev, 15, 2177-2196.
Alexandrova, A., Ivanov, A., Chumakov, P., Kopnin, B. and Vasiliev, J. (2000) Changes in p53 expression in mouse fibroblasts can modify motility and extracellular matrix organization. Oncogene, 19, 5826-5830.
Aljada, A., Ghanim, H., Mohanty, P., Hofmeyer, D., Tripathy, D. and Dandona, P. (2001) Hydrocortisone suppresses intranuclear activator-protein-1 (AP-1) binding activity in mononuclear cells and plasma matrix metalloproteinase 2 and 9 (MMP-2 and MMP-9). J Clin Endocrinol Metab, 86, 5988-5991.
Al-Mohanna, M.A., Al-Khodairy, F.M., Krezolek, Z., Bertilsson, P.A., Al-Houssein, K.A. and Aboussekhra, A. (2001) p53 is dispensable for UV-induced cell cycle arrest at late G(1) in mammalian cells. Carcinogenesis, 22, 573-578.
Araki, N., Morimasa, T., Sakai, T., Tokuoh, H., Yunoue, S., Kamo, M., Miyazaki, K., Abe, K., Saya, H. and Tsugita, A. (2000) Comparative analysis of brain proteins from p53-deficient mice by two-dimensional electrophoresis. Electrophoresis, 21, 1880-1889.
Attardi, L.D., de Vries, A. and Jacks, T. (2004) Activation of the p53-dependent G1 checkpoint response in mouse embryo fibroblasts depends on the specific DNA damage inducer. Oncogene, 23, 973-980.
Barr, P.J. and Tomei, L.D. (1994) Apoptosis and its role in human disease. Biotechnology (N Y), 12, 487-493.
Belani, C.P. (2002) Chemotherapy regimens in advanced non-small-cell lung cancer: recent randomized trials. Clin Lung Cancer, 3 Suppl 1, S5-9.
Benbow, U., Schoenermark, M.P., Orndorff, K.A., Givan, A.L. and Brinckerhoff, C.E. (1999) Human breast cancer cells activate procollagenase-1 and invade type I collagen: invasion is inhibited by all-trans retinoic acid. Clin Exp Metastasis, 17, 231-238.
Bernstein, E., Caudy, A.A., Hammond, S.M. and Hannon, G.J. (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature, 409, 363-366.
Bian, J. and Sun, Y. (1997) Transcriptional activation by p53 of the human type IV collagenase (gelatinase A or matrix metalloproteinase 2) promoter. Mol Cell Biol, 17, 6330-6338.
Bodmer, J.L., Holler, N., Reynard, S., Vinciguerra, P., Schneider, P., Juo, P., Blenis, J. and Tschopp, J. (2000) TRAIL receptor-2 signals apoptosis through FADD and caspase-8. Nat Cell Biol, 2, 241-243.
Bos, J.L. (1989) ras oncogenes in human cancer: a review. Cancer Res, 49, 4682-4689.
Bouck, N. (1996) P53 and angiogenesis. Biochim Biophys Acta, 1287, 63-66.
Brummelkamp, T.R., Bernards, R. and Agami, R. (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science, 296, 550-553.
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J.P., Sedivy, J.M., Kinzler, K.W. and Vogelstein, B. (1998) Requirement for p53 and p21 to sustain G2 arrest after DNA damage. Science, 282, 1497-1501.
Canman, C.E. and Lim, D.S. (1998) The role of ATM in DNA damage responses and cancer. Oncogene, 17, 3301-3308.
Caplen, N.J., Fleenor, J., Fire, A. and Morgan, R.A. (2000) dsRNA-mediated gene silencing in cultured Drosophila cells: a tissue culture model for the analysis of RNA interference. Gene, 252, 95-105.
Chambers, A.F., Groom, A.C. and MacDonald, I.C. (2002) Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer, 2, 563-572.
Chan, T.A., Hermeking, H., Lengauer, C., Kinzler, K.W. and Vogelstein, B. (1999) 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature, 401, 616-620.
Chintala, S.K., Ali-Osman, F., Mohanam, S., Rayford, A., Go, Y., Gokaslan, Z.L., Gagercas, E., Venkaiah, B., Sawaya, R., Nicolson, G.L. and Rao, J.S. (1997) Effect of cisplatin and BCNU on MMP-2 levels in human glioblastoma cell lines in vitro. Clin Exp Metastasis, 15, 361-367.
Clemens, J.C., Worby, C.A., Simonson-Leff, N., Muda, M., Maehama, T., Hemmings, B.A. and Dixon, J.E. (2000) Use of double-stranded RNA interference in Drosophila cell lines to dissect signal transduction pathways. Proc Natl Acad Sci U S A, 97, 6499-6503.
Comer, K.A., Dennis, P.A., Armstrong, L., Catino, J.J., Kastan, M.B. and Kumar, C.C. (1998) Human smooth muscle alpha-actin gene is a transcriptional target of the p53 tumor suppressor protein. Oncogene, 16, 1299-1308.
Conner, E.A., Teramoto, T., Wirth, P.J., Kiss, A., Garfield, S. and Thorgeirsson, S.S. (1999) HGF-mediated apoptosis via p53/bax-independent pathway activating JNK1. Carcinogenesis, 20, 583-590.
Costanzo, V., Robertson, K., Ying, C.Y., Kim, E., Avvedimento, E., Gottesman, M., Grieco, D. and Gautier, J. (2000) Reconstitution of an ATM-dependent checkpoint that inhibits chromosomal DNA replication following DNA damage. Mol Cell, 6, 649-659.
Curran, S. and Murray, G.I. (2000) Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer, 36, 1621-1630.
Dang, C.V. (1999) c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol, 19, 1-11.
DeHaan, R.D., Yazlovitskaya, E.M. and Persons, D.L. (2001) Regulation of p53 target gene expression by cisplatin-induced extracellular signal-regulated kinase. Cancer Chemother Pharmacol, 48, 383-388.
Deverman, B.E., Cook, B.L., Manson, S.R., Niederhoff, R.A., Langer, E.M., Rosova, I., Kulans, L.A., Fu, X., Weinberg, J.S., Heinecke, J.W., Roth, K.A. and Weintraub, S.J. (2002) Bcl-xL deamidation is a critical switch in the regulation of the response to DNA damage. Cell, 111, 51-62.
Elbashir, S.M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K. and Tuschl, T. (2001a) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature, 411, 494-498.
Elbashir, S.M., Lendeckel, W. and Tuschl, T. (2001b) RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev, 15, 188-200.
Elbashir, S.M., Martinez, J., Patkaniowska, A., Lendeckel, W. and Tuschl, T. (2001c) Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. Embo J, 20, 6877-6888.
Falck, J., Mailand, N., Syljuasen, R.G., Bartek, J. and Lukas, J. (2001) The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature, 410, 842-847.
Falck, J., Petrini, J.H., Williams, B.R., Lukas, J. and Bartek, J. (2002) The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat Genet, 30, 290-294.
Fang, L., Li, G., Liu, G., Lee, S.W. and Aaronson, S.A. (2001) p53 induction of heparin-binding EGF-like growth factor counteracts p53 growth suppression through activation of MAPK and PI3K/Akt signaling cascades. Embo J, 20, 1931-1939.
Fanzo, J.C., Reaves, S.K., Cui, L., Zhu, L. and Lei, K.Y. (2002) p53 protein and p21 mRNA levels and caspase-3 activity are altered by zinc status in aortic endothelial cells. Am J Physiol Cell Physiol, 283, C631-638.
Filippov, V., Solovyev, V., Filippova, M. and Gill, S.S. (2000) A novel type of RNase III family proteins in eukaryotes. Gene, 245, 213-221.
Fire, A., Xu, S., Montgomery, M.K., Kostas, S.A., Driver, S.E. and Mello, C.C. (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature, 391, 806-811.
Fisher, D.E. (1994) Apoptosis in cancer therapy: crossing the threshold. Cell, 78, 539-542.
Flatt, P.M., Tang, L.J., Scatena, C.D., Szak, S.T. and Pietenpol, J.A. (2000) p53 regulation of G(2) checkpoint is retinoblastoma protein dependent. Mol Cell Biol, 20, 4210-4223.
Fulda, S., Los, M., Friesen, C. and Debatin, K.M. (1998) Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system. Int J Cancer, 76, 105-114.
Galaktionov, K., Lee, A.K., Eckstein, J., Draetta, G., Meckler, J., Loda, M. and Beach, D. (1995) CDC25 phosphatases as potential human oncogenes. Science, 269, 1575-1577.
Gardner, J. and Ghorpade, A. (2003) Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system. J Neurosci Res, 74, 801-806.
Gatti, L., Supino, R., Perego, P., Pavesi, R., Caserini, C., Carenini, N., Righetti, S.C., Zuco, V. and Zunino, F. (2002) Apoptosis and growth arrest induced by platinum compounds in U2-OS cells reflect a specific DNA damage recognition associated with a different p53-mediated response. Cell Death Differ, 9, 1352-1359.
Giatromanolaki, A. (2001) Prognostic role of angiogenesis in non-small cell lung cancer. Anticancer Res, 21, 4373-4382.
Gonzalez, V.M., Fuertes, M.A., Alonso, C. and Perez, J.M. (2001) Is cisplatin-induced cell death always produced by apoptosis? Mol Pharmacol, 59, 657-663.
Guo, F., Gao, Y., Wang, L. and Zheng, Y. (2003) p19Arf-p53 tumor suppressor pathway regulates cell motility by suppression of phosphoinositide 3-kinase and Rac1 GTPase activities. J Biol Chem, 278, 14414-14419.
Guo, S. and Kemphues, K.J. (1995) par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 81, 611-620.
Haffner, R. and Oren, M. (1995) Biochemical properties and biological effects of p53. Curr Opin Genet Dev, 5, 84-90.
Hammond, S.M., Bernstein, E., Beach, D. and Hannon, G.J. (2000) An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature, 404, 293-296.
Han, J.A., Kim, J.I., Ongusaha, P.P., Hwang, D.H., Ballou, L.R., Mahale, A., Aaronson, S.A. and Lee, S.W. (2002) P53-mediated induction of Cox-2 counteracts p53- or genotoxic stress-induced apoptosis. Embo J, 21, 5635-5644.
Han, J.Y., Hong, E.K., Choi, B.G., Park, J.N., Kim, K.W., Kang, J.H., Jin, J.Y., Park, S.Y., Hong, Y.S. and Lee, K.S. (2003) Death receptor 5 and Bcl-2 protein expression as predictors of tumor response to gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer. Med Oncol, 20, 355-362.
Hannon, G.J. (2002) RNA interference. Nature, 418, 244-251.
He, C.S., Wilhelm, S.M., Pentland, A.P., Marmer, B.L., Grant, G.A., Eisen, A.Z. and Goldberg, G.I. (1989) Tissue cooperation in a proteolytic cascade activating human interstitial collagenase. Proc Natl Acad Sci U S A, 86, 2632-2636.
Hirao, A., Cheung, A., Duncan, G., Girard, P.M., Elia, A.J., Wakeham, A., Okada, H., Sarkissian, T., Wong, J.A., Sakai, T., De Stanchina, E., Bristow, R.G., Suda, T., Lowe, S.W., Jeggo, P.A., Elledge, S.J. and Mak, T.W. (2002) Chk2 is a tumor suppressor that regulates apoptosis in both an ataxia telangiectasia mutated (ATM)-dependent and an ATM-independent manner. Mol Cell Biol, 22, 6521-6532.
Hoshino, R., Tanimura, S., Watanabe, K., Kataoka, T. and Kohno, M. (2001) Blockade of the extracellular signal-regulated kinase pathway induces marked G1 cell cycle arrest and apoptosis in tumor cells in which the pathway is constitutively activated: up-regulation of p27(Kip1). J Biol Chem, 276, 2686-2692.
Hutvagner, G. and Zamore, P.D. (2002) RNAi: nature abhors a double-strand. Curr Opin Genet Dev, 12, 225-232.
Hwang, A. and Muschel, R.J. (1998) Radiation and the G2 phase of the cell cycle. Radiat Res, 150, S52-59.
Imamura, T., Izumi, H., Nagatani, G., Ise, T., Nomoto, M., Iwamoto, Y. and Kohno, K. (2001) Interaction with p53 enhances binding of cisplatin-modified DNA by high mobility group 1 protein. J Biol Chem, 276, 7534-7540.
Innocente, S.A., Abrahamson, J.L., Cogswell, J.P. and Lee, J.M. (1999) p53 regulates a G2 checkpoint through cyclin B1. Proc Natl Acad Sci U S A, 96, 2147-2152.
Johnsen, M., Lund, L.R., Romer, J., Almholt, K. and Dano, K. (1998) Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol, 10, 667-671.
Jorgensen, L.N. (2003) Collagen deposition in the subcutaneous tissue during wound healing in humans: a model evaluation. APMIS Suppl, 1-56.
Kastan, M.B. and Lim, D.S. (2000) The many substrates and functions of ATM. Nat Rev Mol Cell Biol, 1, 179-186.
Ketting, R.F., Fischer, S.E., Bernstein, E., Sijen, T., Hannon, G.J. and Plasterk, R.H. (2001) Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev, 15, 2654-2659.
Kim, D., Kim, S., Koh, H., Yoon, S.O., Chung, A.S., Cho, K.S. and Chung, J. (2001) Akt/PKB promotes cancer cell invasion via increased motility and metalloproteinase production. Faseb J, 15, 1953-1962.
Kischkel, F.C., Lawrence, D.A., Chuntharapai, A., Schow, P., Kim, K.J. and Ashkenazi, A. (2000) Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity, 12, 611-620.
Ko, L.J. and Prives, C. (1996) p53: puzzle and paradigm. Genes Dev, 10, 1054-1072.
Kubiatowski, T., Jang, T., Lachyankar, M.B., Salmonsen, R., Nabi, R.R., Quesenberry, P.J., Litofsky, N.S., Ross, A.H. and Recht, L.D. (2001) Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas. J Neurosurg, 95, 480-488.
Li, P., Nijhawan, D., Budihardjo, I., Srinivasula, S.M., Ahmad, M., Alnemri, E.S. and Wang, X. (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 91, 479-489.
Liabakk, N.B., Talbot, I., Smith, R.A., Wilkinson, K. and Balkwill, F. (1996) Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res, 56, 190-196.
Lieber, M., Smith, B., Szakal, A., Nelson-Rees, W. and Todaro, G. (1976) A continuous tumor-cell line from a human lung carcinoma with properties of type II alveolar epithelial cells. Int J Cancer, 17, 62-70.
Liu, Q., Guntuku, S., Cui, X.S., Matsuoka, S., Cortez, D., Tamai, K., Luo, G., Carattini-Rivera, S., DeMayo, F., Bradley, A., Donehower, L.A. and Elledge, S.J. (2000) Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev, 14, 1448-1459.
Lowe, S.W., Schmitt, E.M., Smith, S.W., Osborne, B.A. and Jacks, T. (1993) p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature, 362, 847-849.
Lu, X., Xie, W., Reed, D., Bradshaw, W.S. and Simmons, D.L. (1995) Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl Acad Sci U S A, 92, 7961-7965.
Ludes-Meyers, J.H., Subler, M.A., Shivakumar, C.V., Munoz, R.M., Jiang, P., Bigger, J.E., Brown, D.R., Deb, S.P. and Deb, S. (1996) Transcriptional activation of the human epidermal growth factor receptor promoter by human p53. Mol Cell Biol, 16, 6009-6019.
Madlener, M., Parks, W.C. and Werner, S. (1998) Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are differentially expressed during excisional skin wound repair. Exp Cell Res, 242, 201-210.
Mailand, N., Falck, J., Lukas, C., Syljuasen, R.G., Welcker, M., Bartek, J. and Lukas, J. (2000) Rapid destruction of human Cdc25A in response to DNA damage. Science, 288, 1425-1429.
Manche, L., Green, S.R., Schmedt, C. and Mathews, M.B. (1992) Interactions between double-stranded RNA regulators and the protein kinase DAI. Mol Cell Biol, 12, 5238-5248.
Matsuoka, S., Huang, M. and Elledge, S.J. (1998) Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science, 282, 1893-1897.
Meerson, A., Milyavsky, M. and Rotter, V. (2004) p53 mediates density-dependent growth arrest. FEBS Lett, 559, 152-158.
Metcalfe, A.M., Dixon, R.M. and Radda, G.K. (1997) Wild-type but not mutant p53 activates the hepatocyte growth factor/scatter factor promoter. Nucleic Acids Res, 25, 983-986.
Minks, M.A., West, D.K., Benvin, S. and Baglioni, C. (1979) Structural requirements of double-stranded RNA for the activation of 2',5'-oligo(A) polymerase and protein kinase of interferon-treated HeLa cells. J Biol Chem, 254, 10180-10183.
Molinari, M., Mercurio, C., Dominguez, J., Goubin, F. and Draetta, G.F. (2000) Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis. EMBO Rep, 1, 71-79.
Muller, A., Homey, B., Soto, H., Ge, N., Catron, D., Buchanan, M.E., McClanahan, T., Murphy, E., Yuan, W., Wagner, S.N., Barrera, J.L., Mohar, A., Verastegui, E. and Zlotnik, A. (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature, 410, 50-56.
Murphy, M., Mabruk, M.J., Lenane, P., Liew, A., McCann, P., Buckley, A., Billet, P., Leader, M., Kay, E. and Murphy, G.M. (2002) The expression of p53, p21, Bax and induction of apoptosis in normal volunteers in response to different doses of ultraviolet radiation. Br J Dermatol, 147, 110-117.
Nagase, H. (1997) Activation mechanisms of matrix metalloproteinases. Biol Chem, 378, 151-160.
Nelson, A.R., Fingleton, B., Rothenberg, M.L. and Matrisian, L.M. (2000) Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol, 18, 1135-1149.
Nykanen, A., Haley, B. and Zamore, P.D. (2001) ATP requirements and small interfering RNA structure in the RNA interference pathway. Cell, 107, 309-321.
O'Neill, T., Giarratani, L., Chen, P., Iyer, L., Lee, C.H., Bobiak, M., Kanai, F., Zhou, B.B., Chung, J.H. and Rathbun, G.A. (2002) Determination of substrate motifs for human Chk1 and hCds1/Chk2 by the oriented peptide library approach. J Biol Chem, 277, 16102-16115.
Osteen, K.G., Yeaman, G.R. and Bruner-Tran, K.L. (2003) Matrix metalloproteinases and endometriosis. Semin Reprod Med, 21, 155-164.
Overall, C.M. and Lopez-Otin, C. (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer, 2, 657-672.
Ozdemir, E., Kakehi, Y., Okuno, H., Habuchi, T., Okada, Y. and Yoshida, O. (1997) Strong correlation of basement membrane degradation with p53 inactivation and/or MDM2 overexpression in superficial urothelial carcinomas. J Urol, 158, 206-211.
Palanki, M.S. (2002) Inhibitors of AP-1 and NF-kappa B mediated transcriptional activation: therapeutic potential in autoimmune diseases and structural diversity. Curr Med Chem, 9, 219-227.
Pan, L., Eckhoff, C. and Brinckerhoff, C.E. (1995) Suppression of collagenase gene expression by all-trans and 9-cis retinoic acid is ligand dependent and requires both RARs and RXRs. J Cell Biochem, 57, 575-589.
Pan, M.R. and Hung, W.C. (2002) Nonsteroidal anti-inflammatory drugs inhibit matrix metalloproteinase-2 via suppression of the ERK/Sp1-mediated transcription. J Biol Chem, 277, 32775-32780.
Park, B.K., Zeng, X. and Glazer, R.I. (2001) Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer Res, 61, 7647-7653.
Philip, S., Bulbule, A. and Kundu, G.C. (2001) Osteopontin stimulates tumor growth and activation of promatrix metalloproteinase-2 through nuclear factor-kappa B-mediated induction of membrane type 1 matrix metalloproteinase in murine melanoma cells. J Biol Chem, 276, 44926-44935.
Philips, N., Keller, T. and Gonzalez, S. (2004) TGF beta-like regulation of matrix metalloproteinases by anti-transforming growth factor-beta, and anti-transforming growth factor-beta1 antibodies in dermal fibroblasts: Implications for wound healing. Wound Repair Regen, 12, 53-59.
Rotman, G. and Shiloh, Y. (1999) ATM: a mediator of multiple responses to genotoxic stress. Oncogene, 18, 6135-6144.
Sablina, A.A., Chumakov, P.M. and Kopnin, B.P. (2003) Tumor suppressor p53 and its homologue p73alpha affect cell migration. J Biol Chem, 278, 27362-27371.
Sanchez, Y., Wong, C., Thoma, R.S., Richman, R., Wu, Z., Piwnica-Worms, H. and Elledge, S.J. (1997) Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science, 277, 1497-1501.
Sen, S. (1992) Programmed cell death: concept, mechanism and control. Biol Rev Camb Philos Soc, 67, 287-319.
Sherr, C.J. and Roberts, J.M. (1995) Inhibitors of mammalian G1 cyclin-dependent kinases. Genes Dev, 9, 1149-1163.
Shieh, S.Y., Ahn, J., Tamai, K., Taya, Y. and Prives, C. (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev, 14, 289-300.
Shiraishi, K., Fukuda, S., Mori, T., Matsuda, K., Yamaguchi, T., Tanikawa, C., Ogawa, M., Nakamura, Y. and Arakawa, H. (2000) Identification of fractalkine, a CX3C-type chemokine, as a direct target of p53. Cancer Res, 60, 3722-3726.
Sorensen, C.S., Syljuasen, R.G., Falck, J., Schroeder, T., Ronnstrand, L., Khanna, K.K., Zhou, B.B., Bartek, J. and Lukas, J. (2003) Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Cancer Cell, 3, 247-258.
Sprick, M.R., Weigand, M.A., Rieser, E., Rauch, C.T., Juo, P., Blenis, J., Krammer, P.H. and Walczak, H. (2000) FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity, 12, 599-609.
Stark, G.R., Kerr, I.M., Williams, B.R., Silverman, R.H. and Schreiber, R.D. (1998) How cells respond to interferons. Annu Rev Biochem, 67, 227-264.
Stewart, Z.A. and Pietenpol, J.A. (2001) p53 Signaling and cell cycle checkpoints. Chem Res Toxicol, 14, 243-263.
Svoboda, P., Stein, P., Hayashi, H. and Schultz, R.M. (2000) Selective reduction of dormant maternal mRNAs in mouse oocytes by RNA interference. Development, 127, 4147-4156.
Takisawa, H., Mimura, S. and Kubota, Y. (2000) Eukaryotic DNA replication: from pre-replication complex to initiation complex. Curr Opin Cell Biol, 12, 690-696.
Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y. and Nakamura, Y. (2000) A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature, 404, 42-49.
Tang, D., Wu, D., Hirao, A., Lahti, J.M., Liu, L., Mazza, B., Kidd, V.J., Mak, T.W. and Ingram, A.J. (2002) ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem, 277, 12710-12717.
Taylor, W.R., DePrimo, S.E., Agarwal, A., Agarwal, M.L., Schonthal, A.H., Katula, K.S. and Stark, G.R. (1999) Mechanisms of G2 arrest in response to overexpression of p53. Mol Biol Cell, 10, 3607-3622.
Trimmer, E.E. and Essigmann, J.M. (1999) Cisplatin. Essays Biochem, 34, 191-211.
Ui-Tei, K., Zenno, S., Miyata, Y. and Saigo, K. (2000) Sensitive assay of RNA interference in Drosophila and Chinese hamster cultured cells using firefly luciferase gene as target. FEBS Lett, 479, 79-82.
Vojta, P.J. and Barrett, J.C. (1995) Genetic analysis of cellular senescence. Biochim Biophys Acta, 1242, 29-41.
Walworth, N.C. (2000) Cell-cycle checkpoint kinases: checking in on the cell cycle. Curr Opin Cell Biol, 12, 697-704.
Wang, X., Mori, T., Jung, J.C., Fini, M.E. and Lo, E.H. (2002) Secretion of matrix metalloproteinase-2 and -9 after mechanical trauma injury in rat cortical cultures and involvement of MAP kinase. J Neurotrauma, 19, 615-625.
Wang, X.W., Zhan, Q., Coursen, J.D., Khan, M.A., Kontny, H.U., Yu, L., Hollander, M.C., O'Connor, P.M., Fornace, A.J., Jr. and Harris, C.C. (1999) GADD45 induction of a G2/M cell cycle checkpoint. Proc Natl Acad Sci U S A, 96, 3706-3711.
Webb, C.P., Taylor, G.A., Jeffers, M., Fiscella, M., Oskarsson, M., Resau, J.H. and Vande Woude, G.F. (1998) Evidence for a role of Met-HGF/SF during Ras-mediated tumorigenesis/metastasis. Oncogene, 17, 2019-2025.
Welch, D.R., Sakamaki, T., Pioquinto, R., Leonard, T.O., Goldberg, S.F., Hon, Q., Erikson, R.L., Rieber, M., Rieber, M.S., Hicks, D.J., Bonventre, J.V. and Alessandrini, A. (2000) Transfection of constitutively active mitogen-activated protein/extracellular signal-regulated kinase kinase confers tumorigenic and metastatic potentials to NIH3T3 cells. Cancer Res, 60, 1552-1556.
Westermarck, J. and Kahari, V.M. (1999) Regulation of matrix metalloproteinase expression in tumor invasion. Faseb J, 13, 781-792.
Wianny, F. and Zernicka-Goetz, M. (2000) Specific interference with gene function by double-stranded RNA in early mouse development. Nat Cell Biol, 2, 70-75.
Xiong, Y. (1996) Why are there so many CDK inhibitors? Biochim Biophys Acta, 1288, 01-05.
Xu, Y.P., Zhao, X.Q., Sommer, K. and Moubayed, P. (2003) Correlation of matrix metalloproteinase-2, -9, tissue inhibitor-1 of matrix metalloproteinase and CD44 variant 6 in head and neck cancer metastasis. J Zhejiang Univ Sci, 4, 491-501.
Yoshida, M., Korfhagen, T.R. and Whitsett, J.A. (2001) Surfactant protein D regulates NF-kappa B and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways. J Immunol, 166, 7514-7519.
Zamore, P.D. (2001) RNA interference: listening to the sound of silence. Nat Struct Biol, 8, 746-750.
Zamore, P.D., Tuschl, T., Sharp, P.A. and Bartel, D.P. (2000) RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell, 101, 25-33.
Zhang, Y., Thant, A.A., Machida, K., Ichigotani, Y., Naito, Y., Hiraiwa, Y., Senga, T., Sohara, Y., Matsuda, S. and Hamaguchi, M. (2002) Hyaluronan-CD44s signaling regulates matrix metalloproteinase-2 secretion in a human lung carcinoma cell line QG90. Cancer Res, 62, 3962-3965.
Zhou, B.B. and Elledge, S.J. (2000) The DNA damage response: putting checkpoints in perspective. Nature, 408, 433-439.
Boolbol, S.K., Dannenberg, A.J., Chadburn, A., Martucci, C., Guo, X.J., Ramonetti, J.T., Abreu-Goris, M., Newmark, H.L., Lipkin, M.L., DeCosse, J.J. and Bertagnolli, M.M. (1996) Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res, 56, 2556-2560.
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.
Cavallaro, U. and Christofori, G. (2001) Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim Biophys Acta, 1552, 39-45.
Curran, S. and Murray, G.I. (2000) Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer, 36, 1621-1630.
Demidenko, Z.N. and Blagosklonny, M.V. (2004) Flavopiridol induces p53 via initial inhibition of Mdm2 and p21 and, independently of p53, sensitizes apoptosis-reluctant cells to tumor necrosis factor. Cancer Res, 64, 3653-3660.
Di Pietro, R., Centurione, L., Sabatini, N., Bosco, D., Sancilio, S., Garaci, F., Rana, R. and Cataldi, A. (2004) Caspase-3 is dually regulated by apoptogenic factors mitochondrial release and by SAPK/JNK metabolic pathway in leukemic cells exposed to etoposide-ionizing radiation combined treatment. Int J Immunopathol Pharmacol, 17, 181-190.
Ellenrieder, V., Adler, G. and Gress, T.M. (1999) Invasion and metastasis in pancreatic cancer. Ann Oncol, 10 Suppl 4, 46-50.
Hsu, C.-i. (1996) Study on the Fungal Immunomodulatory Proteins. Department of Medical Technology, college of medicine. National Taiwan University, Taipei.
Johnsen, M., Lund, L.R., Romer, J., Almholt, K. and Dano, K. (1998) Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol, 10, 667-671.
Liabakk, N.B., Talbot, I., Smith, R.A., Wilkinson, K. and Balkwill, F. (1996) Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res, 56, 190-196.
Lu, X., Xie, W., Reed, D., Bradshaw, W.S. and Simmons, D.L. (1995) Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl Acad Sci U S A, 92, 7961-7965.
Peebles, R.S., Jr., Dworski, R., Collins, R.D., Jarzecka, K., Mitchell, D.B., Graham, B.S. and Sheller, J.R. (2000) Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice. Am J Respir Crit Care Med, 162, 676-681.
Seidel, B., Braeg, S., Adler, G., Wedlich, D. and Menke, A. (2004) E- and N-cadherin differ with respect to their associated p120(ctn) isoforms and their ability to suppress invasive growth in pancreatic cancer cells. Oncogene.
Sekiguchi, I., Suzuki, M., Tamada, T., Shinomiya, N., Tsuru, S. and Murata, M. (1996) Effects of cisplatin on cell cycle kinetics, morphological change, and cleavage pattern of DNA in two human ovarian carcinoma cell lines. Oncology, 53, 19-26.
Yoon, S.O., Kim, M.M. and Chung, A.S. (2001) Inhibitory effect of selenite on invasion of HT1080 tumor cells. J Biol Chem, 276, 20085-20092.
Alvarez, O.A., Carmichael, D.F. and DeClerck, Y.A. (1990) Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst, 82, 589-595.
Apte, S.S., Olsen, B.R. and Murphy, G. (1995) The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem, 270, 14313-14318.
Ausiello, C.M., Spagnoli, G.C., Boccanera, M., Casalinuovo, I., Malavasi, F., Casciani, C.U. and Cassone, A. (1986) Proliferation of human peripheral blood mononuclear cells induced by Candida albicans and its cell wall fractions. J Med Microbiol, 22, 195-202.
Boller, K., Vestweber, D. and Kemler, R. (1985) Cell-adhesion molecule uvomorulin is localized in the intermediate junctions of adult intestinal epithelial cells. J Cell Biol, 100, 327-332.
Boolbol, S.K., Dannenberg, A.J., Chadburn, A., Martucci, C., Guo, X.J., Ramonetti, J.T., Abreu-Goris, M., Newmark, H.L., Lipkin, M.L., DeCosse, J.J. and Bertagnolli, M.M. (1996) Cyclooxygenase-2 overexpression and tumor formation are blocked by sulindac in a murine model of familial adenomatous polyposis. Cancer Res, 56, 2556-2560.
Boone, T.C., Johnson, M.J., De Clerck, Y.A. and Langley, K.E. (1990) cDNA cloning and expression of a metalloproteinase inhibitor related to tissue inhibitor of metalloproteinases. Proc Natl Acad Sci U S A, 87, 2800-2804.
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.
Cao, L.Z. and Lin, Z.B. (2003) Regulatory effect of Ganoderma lucidum polysaccharides on cytotoxic T-lymphocytes induced by dendritic cells in vitro. Acta Pharmacol Sin, 24, 321-326.
Cavallaro, U. and Christofori, G. (2001) Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim Biophys Acta, 1552, 39-45.
Chen, H.L., Li, D.F., Chang, B.Y., Gong, L.M., Piao, X.S., Yi, G.F. and Zhang, J.X. (2003) Effects of lentinan on broiler splenocyte proliferation, interleukin-2 production, and signal transduction. Poult Sci, 82, 760-766.
Chen, H.Y., Chen, C.H., Yeh, M.Y., Wu, J.S., Yazama, K. and Mikami, Y. (1992) In vivo anti-candidal activity induced by tranditional Chinese herbal medicine, Ganoderma lucidium. Jpn. J. Med. Mycol., 33, 505-512.
Curran, S. and Murray, G.I. (2000) Matrix metalloproteinases: molecular aspects of their roles in tumour invasion and metastasis. Eur J Cancer, 36, 1621-1630.
De Clerck, Y., Szpirer, C., Aly, M.S., Cassiman, J.J., Eeckhout, Y. and Rousseau, G. (1992) The gene for tissue inhibitor of metalloproteinases-2 is localized on human chromosome arm 17q25. Genomics, 14, 782-784.
DeClerck, Y.A., Perez, N., Shimada, H., Boone, T.C., Langley, K.E. and Taylor, S.M. (1992) Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res, 52, 701-708.
Demidenko, Z.N. and Blagosklonny, M.V. (2004) Flavopiridol induces p53 via initial inhibition of Mdm2 and p21 and, independently of p53, sensitizes apoptosis-reluctant cells to tumor necrosis factor. Cancer Res, 64, 3653-3660.
Di Pietro, R., Centurione, L., Sabatini, N., Bosco, D., Sancilio, S., Garaci, F., Rana, R. and Cataldi, A. (2004) Caspase-3 is dually regulated by apoptogenic factors mitochondrial release and by SAPK/JNK metabolic pathway in leukemic cells exposed to etoposide-ionizing radiation combined treatment. Int J Immunopathol Pharmacol, 17, 181-190.
Dietrich, G., Viret, J.F. and Hess, J. (2003) Novel vaccination strategies based on recombinant Mycobacterium bovis BCG. Int J Med Microbiol, 292, 441-451.
Ellenrieder, V., Adler, G. and Gress, T.M. (1999) Invasion and metastasis in pancreatic cancer. Ann Oncol, 10 Suppl 4, 46-50.
Flenniken, A.M. and Williams, B.R. (1990) Developmental expression of the endogenous TIMP gene and a TIMP-lacZ fusion gene in transgenic mice. Genes Dev, 4, 1094-1106.
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.
Fuggetta, M.P., D'Onofrio, C. and Bonmassar, E. (1990) Role of biological response modifiers in immunochemotherapy of solid tumors and retroviral-induced leukemia. Ann Ist Super Sanita, 26, 385-395.
Gabius, H.J., Walzel, H., Joshi, S.S., Kruip, J., Kojima, S., Gerke, V., Kratzin, H. and Gabius, S. (1992) The immunomodulatory beta-galactoside-specific lectin from mistletoe: partial sequence analysis, cell and tissue binding, and impact on intracellular biosignalling of monocytic leukemia cells. Anticancer Res, 12, 669-675.
Goldberg, G.I., Strongin, A., Collier, I.E., Genrich, L.T. and Marmer, B.L. (1992) Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. J Biol Chem, 267, 4583-4591.
Gomez, D.E., Alonso, D.F., Yoshiji, H. and Thorgeirsson, U.P. (1997) Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol, 74, 111-122.
Greene, J., Wang, M., Liu, Y.E., Raymond, L.A., Rosen, C. and Shi, Y.E. (1996) Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem, 271, 30375-30380.
Haak-Frendscho, M., Kino, K., Sone, T. and Jardieu, P. (1993) Ling Zhi-8: a novel T cell mitogen induces cytokine production and upregulation of ICAM-1 expression. Cell Immunol, 150, 101-113.
Hanahan, D. and Weinberg, R.A. (2000) The hallmarks of cancer. Cell, 100, 57-70.
Hikino, H., Konno, C., Mirin, Y. and Hayashi, T. (1985) Isolation and hypoglycemic activity of ganoderans A and B, glycans of Ganoderma lucidum fruit bodies. Planta Med, 339-340.
Hofmann, G.E., Glatstein, I., Schatz, F., Heller, D. and Deligdisch, L. (1994) Immunohistochemical localization of urokinase-type plasminogen activator and the plasminogen activator inhibitors 1 and 2 in early human implantation sites. Am J Obstet Gynecol, 170, 671-676.
Horner, W.E., Helbling, A. and Lehrer, S.B. (1993) Basidiomycete allergens: comparison of three Ganoderma species. Allergy, 48, 110-116.
Hsu, C.-i. (1996) Study on the Fungal Immunomodulatory Proteins. Department of Medical Technology, college of medicine. National Taiwan University, Taipei.
Huebner, K., Isobe, M., Gasson, J.C., Golde, D.W. and Croce, C.M. (1986) Localization of the gene encoding human erythroid-potentiating activity to chromosome region Xp11.1----Xp11.4. Am J Hum Genet, 38, 819-826.
Irazoqui, F.J., Zalazar, F.E., Nores, G.A. and Vides, M.A. (1997) Agaricus bisporus lectin binds mainly O-glycans but also N-glycans of human IgA subclasses. Glycoconj J, 14, 313-319.
Irimura, T., McIsaac, A.M., Carlson, D.A., Yagita, M., Grimm, E.A., Menter, D.G., Ota, D.M. and Clary, K.R. (1990) Soluble factor in normal tissues that stimulates high-molecular-weight sialoglycoprotein production by human colon carcinoma cells. Cancer Res, 50, 3331-3338.
Johnsen, M., Lund, L.R., Romer, J., Almholt, K. and Dano, K. (1998) Cancer invasion and tissue remodeling: common themes in proteolytic matrix degradation. Curr Opin Cell Biol, 10, 667-671.
Johnson, M.D., Kim, H.R., Chesler, L., Tsao-Wu, G., Bouck, N. and Polverini, P.J. (1994) Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol, 160, 194-202.
Kawagishi, H., Fukuhara, F., Sazuka, M., Kawashima, A., Mitsubori, T. and Tomita, T. (1993) 5'-Deoxy-5'-methylsulphinyladenosine, a platelet aggregation inhibitor from Ganoderma lucidium. Phytochemistry, 32, 239-241.
Kawagishi, H., Mori, H., Uno, A., Kimura, A. and Chiba, S. (1994) A sialic acid-binding lectin from the mushroom Hericium erinaceum. FEBS Lett, 340, 56-58.
Kimura, Y., Taniguchi, M. and Baba, K. (2002) Antitumor and antimetastatic effects on liver of triterpenoid fractions of Ganoderma lucidum: mechanism of action and isolation of an active substance. Anticancer Res, 22, 3309-3318.
Kino, K., Yamashita, A., Yamaoka, K., Watanabe, J., Tanaka, S., Ko, K., Shimizu, K. and Tsunoo, H. (1989) Isolation and characterization of a new immunomodulatory protein, ling zhi-8 (LZ-8), from Ganoderma lucidium. J Biol Chem, 264, 472-478.
Ko, J.L., Hsu, C.I., Lin, R.H., Kao, C.L. and Lin, J.Y. (1995) A new fungal immunomodulatory protein, FIP-fve isolated from the edible mushroom, Flammulina velutipes and its complete amino acid sequence. Eur J Biochem, 228, 244-249.
Kolkenbrock, H., Orgel, D., Hecker-Kia, A., Zimmermann, J. and Ulbrich, N. (1995) Generation and activity of the ternary gelatinase B/TIMP-1/LMW-stromelysin-1 complex. Biol Chem Hoppe Seyler, 376, 495-500.
Konska, G., Guillot, J., Dusser, M., Damez, M. and Botton, B. (1994) Isolation and characterization of an N-acetyllactosamine-binding lectin from the mushroom Laetiporus sulfureus. J Biochem (Tokyo), 116, 519-523.
Kugler, A. (1999) Matrix metalloproteinases and their inhibitors. Anticancer Res, 19, 1589-1592.
Leco, K.J., Khokha, R., Pavloff, N., Hawkes, S.P. and Edwards, D.R. (1994) Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem, 269, 9352-9360.
Liabakk, N.B., Talbot, I., Smith, R.A., Wilkinson, K. and Balkwill, F. (1996) Matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9) type IV collagenases in colorectal cancer. Cancer Res, 56, 190-196.
Lin, J.M., Lin, C.C., Chiu, H.F., Yang, J.J. and Lee, S.G. (1993) Evaluation of the anti-inflammatory and liver-protective effects of anoectochilus formosanus, ganoderma lucidum and gynostemma pentaphyllum in rats. Am J Chin Med, 21, 59-69.
Lin, W.H. (1996) Molecular cloning, expression and site-directed mutagenesis of fungal immunomodulatory protein, FIP-gts, from ganoderma tsugae. Graduated Institute of Biochemistry and Molecularboilogy, college of medicine. National Taiwan University, Taipei.
Lin, W.H., Hung, C.H., Hsu, C.I. and Lin, J.Y. (1997) Dimerization of the N-terminal amphipathic alpha-helix domain of the fungal immunomodulatory protein from Ganoderma tsugae (Fip-gts) defined by a yeast two-hybrid system and site-directed mutagenesis. J Biol Chem, 272, 20044-20048.
Lu, X., Xie, W., Reed, D., Bradshaw, W.S. and Simmons, D.L. (1995) Nonsteroidal antiinflammatory drugs cause apoptosis and induce cyclooxygenases in chicken embryo fibroblasts. Proc Natl Acad Sci U S A, 92, 7961-7965.
Min, B.S., Gao, J.J., Hattori, M., Lee, H.K. and Kim, Y.H. (2001) Anticomplement activity of terpenoids from the spores of Ganoderma lucidum. Planta Med, 67, 811-814.
Miyasaka, N., Inoue, H., Totsuka, T., Koike, R., Kino, K. and Tsunoo, H. (1992) An immunomodulatory protein, Ling Zhi-8, facilitates cellular interaction through modulation of adhesion molecules. Biochem Biophys Res Commun, 186, 385-390.
Murphy, G., Reynolds, J.J. and Hembry, R.M. (1989) Metalloproteinases and cancer invasion and metastasis. Int J Cancer, 44, 757-760.
O'Donoghue, G.V., Okarma, T.B. and Lee, Y.M. (1993) An immune complex selective affinity column utilizing site-specific attachment of bovine conglutinin. Anal Biochem, 213, 310-317.
Patocka, J. (1999) Anti-inflammatory triterpenoids from mysterious mushroom Ganoderma lucidum and their potential possibility in modern medicine. Acta Medica (Hradec Kralove), 42, 123-125.
Peebles, R.S., Jr., Dworski, R., Collins, R.D., Jarzecka, K., Mitchell, D.B., Graham, B.S. and Sheller, J.R. (2000) Cyclooxygenase inhibition increases interleukin 5 and interleukin 13 production and airway hyperresponsiveness in allergic mice. Am J Respir Crit Care Med, 162, 676-681.
Romer, J., Bugge, T.H., Pyke, C., Lund, L.R., Flick, M.J., Degen, J.L. and Dano, K. (1996) Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med, 2, 287-292.
Seidel, B., Braeg, S., Adler, G., Wedlich, D. and Menke, A. (2004) E- and N-cadherin differ with respect to their associated p120(ctn) isoforms and their ability to suppress invasive growth in pancreatic cancer cells. Oncogene.
Sekiguchi, I., Suzuki, M., Tamada, T., Shinomiya, N., Tsuru, S. and Murata, M. (1996) Effects of cisplatin on cell cycle kinetics, morphological change, and cleavage pattern of DNA in two human ovarian carcinoma cell lines. Oncology, 53, 19-26.
Shapiro, S.D., Kobayashi, D.K. and Welgus, H.G. (1992) Identification of TIMP-2 in human alveolar macrophages. Regulation of biosynthesis is opposite to that of metalloproteinases and TIMP-1. J Biol Chem, 267, 13890-13894.
Shimizu, A., Yano, T., Saito, Y. and Inada, Y. (1985) Isolation of an inhibitor of platelet aggregation from a fungus, Ganoderma lucidum. Chem Pharm Bull (Tokyo), 33, 3012-3015.
Sliva, D., Rizzo, M.T. and English, D. (2002) Phosphatidylinositol 3-kinase and NF-kappaB regulate motility of invasive MDA-MB-231 human breast cancer cells by the secretion of urokinase-type plasminogen activator. J Biol Chem, 277, 3150-3157.
Stetler-Stevenson, W.G., Brown, P.D., Onisto, M., Levy, A.T. and Liotta, L.A. (1990) Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. J Biol Chem, 265, 13933-13938.
Stricklin, G.P. and Welgus, H.G. (1983) Human skin fibroblast collagenase inhibitor. Purification and biochemical characterization. J Biol Chem, 258, 12252-12258.
Takeichi, M. (1991) Cadherin cell adhesion receptors as a morphogenetic regulator. Science, 251, 1451-1455.
Takigawa, M., Nishida, Y., Suzuki, F., Kishi, J., Yamashita, K. and Hayakawa, T. (1990) Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP and TIMP-2). Biochem Biophys Res Commun, 171, 1264-1271.
Tandon, P. and Diamond, S.L. (1998) Kinetics of beta2-integrin and L-selectin bonding during neutrophil aggregation in shear flow. Biophys J, 75, 3163-3178.
Thorgeirsson, U.P., Yoshiji, H., Sinha, C.C. and Gomez, D.E. (1996) Breast cancer; tumor neovasculature and the effect of tissue inhibitor of metalloproteinases-1 (TIMP-1) on angiogenesis. In Vivo, 10, 137-144.
Ueno, Y., Kohgo, Y., Sakamaki, S., Itoh, Y., Takahashi, M., Hirayama, Y. and Niitsu, Y. (1994) Immunochemotherapy in B-16-melanoma-cell-transplanted mice with combinations of interleukin-2, cyclophosphamide, and PSK. Oncology, 51, 296-302.
van der Hem, L.G., van der Vliet, J.A., Bocken, C.F., Kino, K., Hoitsma, A.J. and Tax, W.J. (1995) Ling Zhi-8: studies of a new immunomodulating agent. Transplantation, 60, 438-443.
Wang, S.Y., Hsu, M.L., Hsu, H.C., Tzeng, C.H., Lee, S.S., Shiao, M.S. and Ho, C.K. (1997) The anti-tumor effect of Ganoderma lucidum is mediated by cytokines released from activated macrophages and T lymphocytes. Int J Cancer, 70, 699-705.
Wang, Y.Y., Khoo, K.H., Chen, S.T., Lin, C.C., Wong, C.H. and Lin, C.H. (2002) Studies on the immuno-modulating and antitumor activities of Ganoderma lucidum (Reishi) polysaccharides: functional and proteomic analyses of a fucose-containing glycoprotein fraction responsible for the activities. Bioorg Med Chem, 10, 1057-1062.
Wick, M., Burger, C., Brusselbach, S., Lucibello, F.C. and Muller, R. (1994) A novel member of human tissue inhibitor of metalloproteinases (TIMP) gene family is regulated during G1 progression, mitogenic stimulation, differentiation, and senescence. J Biol Chem, 269, 18953-18960.
Woessner, J.F., Jr. (1991) Matrix metalloproteinases and their inhibitors in connective tissue remodeling. Faseb J, 5, 2145-2154.
Yang, T.T. and Hawkes, S.P. (1992) Role of the 21-kDa protein TIMP-3 in oncogenic transformation of cultured chicken embryo fibroblasts. Proc Natl Acad Sci U S A, 89, 10676-10680.
Yasunari, K., Kohno, M., Hasuma, T., Horio, T., Kano, H., Yokokawa, K., Minami, M. and Yoshikawa, J. (1997) Dopamine as a novel antimigration and antiproliferative factor of vascular smooth muscle cells through dopamine D1-like receptors. Arterioscler Thromb Vasc Biol, 17, 3164-3173.
Yoon, S.O., Kim, M.M. and Chung, A.S. (2001) Inhibitory effect of selenite on invasion of HT1080 tumor cells. J Biol Chem, 276, 20085-20092.
Zhang, G.L., Wang, Y.H., Ni, W., Teng, H.L. and Lin, Z.B. (2002) Hepatoprotective role of Ganoderma lucidum polysaccharide against BCG-induced immune liver injury in mice. World J Gastroenterol, 8, 728-733.