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系統識別號 U0026-0402201014401600
論文名稱(中文) 鑑定T細胞淋巴癌侵略和轉移基因2(TIAM2)在肝癌的角色
論文名稱(英文) Characterization of the Role of T-Cell Lymphoma Invasion and Metastasis 2 (TIAM2) in Hepatocellular Carcinoma
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 98
學期 1
出版年 99
研究生(中文) 陳嘉興
研究生(英文) Jia-Shing Chen
學號 s5890102
學位類別 博士
語文別 英文
論文頁數 107頁
口試委員 指導教授-孫孝芳
口試委員-蘇益仁
口試委員-蔡少正
口試委員-楊倍昌
口試委員-呂昱瑋
口試委員-蔡世峰
中文關鍵字 肝癌  增生  侵略  裸鼠 
英文關鍵字 TIAM2  hepatocellular carcinoma  biomarker  proliferation  invasion  nude mice 
學科別分類
中文摘要 T細胞侵犯和轉移蛋白2(T-Cell Invasion and Metastasis 2; 簡稱TIAM2)是人類T細胞侵犯和轉移蛋白1(T-Cell Invasion and Metastasis 1; 簡稱TIAM1)的同源基因, Tiam1是Rac特異的鳥核甘酸交換因子,參與在神經的發育過程中。在許多惡性腫瘤中TIAM1的表現異常。目前TIAM2在生理及病理上的功能仍不清楚。研究鑑定人類TIAM2蛋白的功能並揭示TIAM2 異構體 (TIAM2S)在肝癌細胞癌化過程的角色。雖然有多個的TIAM2的異構體表現在不同的正常人類組織中,但是只有TIAM2S蛋白表現於人類腦部特定區域。在細胞內TIAM2S不具有傳統鳥核甘酸交換因子活性,此結果暗示人類TIAM2S的功能應該不同於其他TIAM家族成員。雖然TIAM2在正常的肝組職及良性的肝臟血管瘤中不表現,但是82% (73/89)肝癌細胞檢體及轉移到其他部位的肝癌細胞檢體中可偵測到TIAM2S的表現。當表現TIAM2S於癌化程度較低的肝癌細胞株HepG2中,會促使它轉化成具有高增生能力及高侵犯能力的細胞。在裸鼠體內移植表現TIAM2S的HepG2細胞株所形成的腫瘤,會侵入鄰近腫瘤的肌肉組織。由這些異體移植腫瘤所衍生出來的初代培養細胞株,會表現高量的N-cadherin蛋白。總結這些研究結果我們認為TIAM2S是一個新的肝癌的致癌基因。肝細胞表現TIAM2S之後可促進細胞增生及侵犯鄰近組織的能力。此外,TIAM2S媒介活化N-cadherin表現的訊息傳遞路徑也可能參與肝癌細胞癌化的過程。
英文摘要 T-Cell Lymphoma Invasion and Metastasis 2 (TIAM2) gene is the homolog of TIAM1 and ortholog of mouse Stef, both of them are Rac-specific guanine nucleotide exchange factor (GEF). It is well documented that impaired control of TIAM1 expression is involved in different types of malignancies. In contrast, TIAM2 is poorly studied in human. Whether deregulation of the TIAM2 contributes to any types of tumor formation remains to be elucidated. In this study we functionally characterized the human TIAM2 and determined a role of TIAM2S in the tumorigenesis of hepatocellular carcinoma (HCC). Only the short form TIAM2 (TIAM2S) protein was detected in restricted regions of human brain. Functional assays of TIAM2S revealed the protein did not translocate to cell membrane and exhibited no GEF activity in vivo. Thus, the data suggested a distinct role of human TIAM2S from other members of TIAM family. Expression of TIAM2S was undetectable in normal human liver, but it ectopically expressed in all HCC cell lines to variable levels. Ectopic expression of TIAM2S was found in 82% (73/89) paired HCC but not in 30 hemangioma samples. Stable overexpression of TIAM2S promoted the growth and invasion abilities of HepG2 cells. Further in vivo study demonstrated that mice inoculated with HepG2 cells stably expressing TIAM2S developed tumors with invasive phenotype (5/9); while the xenograft tumors from control mice did not show the phenotype. Further examinations demonstrated that TIAM2S expression was associated with up-regulation of N-cadherin in primary cultured tumor cells. Taken together, these findings show, for the first time, that human TIAM2S is a potential oncogene for HCC. Furthermore, the high incidence of ectopic expression of TIAM2S in HCC suggests TIAM2S represents a valuable marker for human HCC.
論文目次 ABSTRACT IN CHINESE------------------------------------I
ABSTRACT IN ENGLISH-----------------------------------II
ACKNOWLEDGEMENTS-------------------------------------III
TABLE OF CONTENTS-------------------------------------IV
LIST OF TABLES---------------------------------------VII
LIST OF FIGURES-------------------------------------VIII
CHAPTER ONE--------------------------------------------1
LITERATURE REVIEW--------------------------------------1
1.1. REGULATION OF RHO GTPASE ACTIVITY-----------------2
1.2. THE DBL HOMOLOGY (DH) DOMAIN DEFINES A FAMILY OF PROTO-ONCOGENES-----------------------------------------3
1.3. TIAM SUBFAMILY: A DBL RELATED GEF SUBGROUP---------3
1.4. CONSERVED DOMAIN ARCHITECTURE IN TIAM SUBFAMILY----4
1.5. T-CELL LYMPHOMA INVASION AND METASTASIS-1 (TIAM1)--4
1.6. SIF AND TIAM1-LIKE EXCHANGE FACTOR (STEF)----------5
1.7. T-CELL LYMPHOMA INVASION AND METASTASIS-2 (TIAM2)--6
1.8. ABERRANT EXPRESSION OF TIAM MEMBERS PARTICIPATE IN CARCINOGENESIS------------------------------------------7
1.9. THE ROLE OF RHO GTPASE IN THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC)--------------------------8
1.10. RESEARCH OBJECTIVE--------------------------------9
CHAPTER TWO--------------------------------------------10
IDENTIFICATION AND FUNCTIONAL CHARACTERIZATION OF T-CELL LYMPHOMA INVASION AND METASTASIS 2 (TIAM2)-------------10
2.1. ABSTRACT------------------------------------------11
2.2. INTRODUCTION--------------------------------------12
2.3. MATERIALS AND METHODS-----------------------------15
2.3.1. Cell Lines---------------------------------------15
2.3.2. RNA Isolation and Quantitative RT-Real-Time PCR--15
2.3.3. Protein Preparation and Antibodies----------------16
2.3.4. Expression Constructs-----------------------------17
2.3.5. Gene Structure and Domain Analysis----------------17
2.3.6. Endogenous TIAM2 Detection------------------------18
2.3.7. Western Blot and Immunohistochemistry-------------19
2.3.8. Protein Identified by Liquid Chromatography-Tandem Mass Spectrometry (LC/MS/MS) Analysis--------------------20
2.3.9. Deglycosylated Analysis of TIAM2S-----------------21
2.3.10. Test of Membrane Association by PDGF Treatment---22
2.3.11. Rho GTPase Pull-Down Assays----------------------22
2.3.12. Statistical Analysis-----------------------------24
2.4. RESULTS---------------------------------------------25
2.4.1. TIAM Family Proteins are Highly Conserved at the C-terminal Region------------------------------------------25
2.4.2. TIAM2 is Tissue Specific Expression Gene----------25
2.4.3. TIAM2S is Expressed in Neurons of Restricted Brain Regions--------------------------------------------------26
2.4.4. TIAM2S is an O-linked Glycoprotein----------------27
2.4.5. TIAM2S Protein has No GEF Activity----------------28
2.5. DISCUSSION------------------------------------------30
2.5.1. TIAM2 is a Distinct Member of TIAM Family---------30
2.5.2. The Cellular Character of TIAM2S Protein is Differ to Other TIAM Members------------------------------------31
CHAPTER THREE--------------------------------------------49
T-CELL LYMPHOMA AND METASTASIS 2 PROMOTES PROLIFERATION AND INVASION IN HEPATOCELLULAR CARCINOMA CELLS-----------49
3.1. ABSTRACT--------------------------------------------50
3.2. INTRODUCTION----------------------------------------51
3.3. MATERIALS AND METHODS-------------------------------53
3.3.1. Specimen and Cell Lines---------------------------53
3.3.2. Semi-quantification of protein expression in HCC--54
3.3.3. Cell Proliferation Assay--------------------------54
3.3.4. Colony Formation Assay----------------------------55
3.3.5. Cell Invasion Assay-------------------------------55
3.3.6. In vivo Tumorigenicity Assay----------------------56
3.3.7. Primary Culture of Xenograft Tumor----------------56
3.3.8. Statistical Analysis------------------------------57
3.4. RESULTS---------------------------------------------58
3.4.1. Ectopic Expression of TIAM2S in Liver Cancers-----58
3.4.2. TIAM2S Expression Promotes Cell Growth and Invasion -------------------------------------------------59
3.4.3. TIAM2S Enhances Invasion Ability of Xenograft Tumors in Nude Mice--------------------------------------60
3.4.4. Up-regulated N-cadherin in TIAM2S Expressed Primary Culture Cells--------------------------------------------61
3.5. DISCUSSION------------------------------------------62
3.5.1. Ectopic TIAM2S Expression Promotes Cell Growth and Invasion in vitro and in vivo----------------------------62
3.5.2. TIAM2S could be New Biomarker for HCC-------------62
3.5.3. The Role of TIAM2S Expression in Tumorigenesis of HCC------------------------------------------------------63
CHAPTER FOUR---------------------------------------------81
GENERAL DISCUSSION AND CONCLUSION------------------------81
4.1. SUMMARY OF TIAM2 MOLECULAR FUNCTION-----------------82
4. 2. THE FUNCTION OF TIAM2S IN HUMAN BRAIN--------------82
4.3. THE TIAM2S CELLULAR EFFECT INVOLVES IN CARCINOGENESIS OF HCC---------------------------------------------------83
4.4. TIAM2S, A USEFUL BIOMARKER FOR HCC------------------85
4.5. TIAM2S, A GEF OR NOT A GEF--------------------------85
REFERENCES-----------------------------------------------87
APPENDIX FIGURES-----------------------------------------92
Appendix Figure 1. TIAM2 expression in human normal and tumor cDNAs.---------------------------------------------93
Appendix figure 2. TIAM2S protein is ectopically expressed in HCC cells.----------------------------------96
Appendix figure 3. TIAM2S protein is not expressed in benign hemangioma.---------------------------------------97
Appendix figure 4. Potential PTM sites in TIAM2S protein. -------------------------------------------------99
Appendix figure 5. Working model-----------------------100
APPENDIX TABLES-----------------------------------------101
Appendix Table 1. Detailed information of each HCC patients ------------------------------------------------102
Appendix Table 2. Primer used in this study-------------107

參考文獻 Arias, A.M. (2001) Epithelial mesenchymal interactions in cancer and development. Cell, 105, 425-431.
Birchmeier, W., Behrens, J., Weidner, K.M., Hulsken, J. and Birchmeier, C. (1996) Epithelial differentiation and the control of metastasis in carcinomas. Curr Top Microbiol Immunol, 213 ( Pt 2), 117-135.
Bishop, A.L. and Hall, A. (2000) Rho GTPases and their effector proteins. Biochem J, 348 Pt 2, 241-255.
Bosch, F.X., Ribes, J., Diaz, M. and Cleries, R. (2004) Primary liver cancer: worldwide incidence and trends. Gastroenterology, 127, S5-S16.
Buchanan, F.G., Elliot, C.M., Gibbs, M. and Exton, J.H. (2000) Translocation of the Rac1 guanine nucleotide exchange factor Tiam1 induced by platelet-derived growth factor and lysophosphatidic acid. J Biol Chem, 275, 9742-9748.
Caldwell, S. and Park, S.H. (2009) The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology. J Gastroenterol, 44 Suppl 19, 96-101.
Cha, C. and Dematteo, R.P. (2005) Molecular mechanisms in hepatocellular carcinoma development. Best Pract Res Clin Gastroenterol, 19, 25-37.
Cheng, J.C., Chou, C.H., Kuo, M.L. and Hsieh, C.Y. (2006) Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF-kappaB signal transduction pathway. Oncogene, 25, 7009-7018.
Chiu, C.Y., Leng, S., Martin, K.A., Kim, E., Gorman, S. and Duhl, D.M. (1999) Cloning and characterization of T-cell lymphoma invasion and metastasis 2 (TIAM2), a novel guanine nucleotide exchange factor related to TIAM1. Genomics, 61, 66-73.
Chung, T.W., Lee, Y.C. and Kim, C.H. (2004) Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. Faseb J, 18, 1123-1125.
Colicelli, J. (2004) Human RAS superfamily proteins and related GTPases. Sci STKE, 2004, RE13.
Daniels, R.H., Zenke, F.T. and Bokoch, G.M. (1999) alphaPix stimulates p21-activated kinase activity through exchange factor-dependent and -independent mechanisms. J Biol Chem, 274, 6047-6050.
de Curtis, I. (2008) Functions of Rac GTPases during neuronal development. Dev Neurosci, 30, 47-58.
Ding, Y., Chen, B., Wang, S., Zhao, L., Chen, J., Ding, Y., Chen, L. and Luo, R. (2009) Overexpression of Tiam1 in hepatocellular carcinomas predicts poor prognosis of HCC patients. Int J Cancer, 124, 653-658.
Ditton, H.J., Zimmer, J., Kamp, C., Rajpert-De Meyts, E. and Vogt, P.H. (2004) The AZFa gene DBY (DDX3Y) is widely transcribed but the protein is limited to the male germ cells by translation control. Hum Mol Genet, 13, 2333-2341.
Engers, R., Mueller, M., Walter, A., Collard, J.G., Willers, R. and Gabbert, H.E. (2006) Prognostic relevance of Tiam1 protein expression in prostate carcinomas. Br J Cancer, 95, 1081-1086.
Engers, R., Zwaka, T.P., Gohr, L., Weber, A., Gerharz, C.D. and Gabbert, H.E. (2000) Tiam1 mutations in human renal-cell carcinomas. Int J Cancer, 88, 369-376.
Eva, A. and Aaronson, S.A. (1985) Isolation of a new human oncogene from a diffuse B-cell lymphoma. Nature, 316, 273-275.
Fransvea, E., Angelotti, U., Antonaci, S. and Giannelli, G. (2008) Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology, 47, 1557-1566.
Fujiyama, S., Tanaka, M., Maeda, S., Ashihara, H., Hirata, R. and Tomita, K. (2002) Tumor markers in early diagnosis, follow-up and management of patients with hepatocellular carcinoma. Oncology, 62 Suppl 1, 57-63.
Glaven, J.A., Whitehead, I.P., Nomanbhoy, T., Kay, R. and Cerione, R.A. (1996) Lfc and Lsc oncoproteins represent two new guanine nucleotide exchange factors for the Rho GTP-binding protein. J Biol Chem, 271, 27374-27381.
Grise, F., Bidaud, A. and Moreau, V. (2009) Rho GTPases in hepatocellular carcinoma. Biochim Biophys Acta, 1795, 137-151.
Habets, G.G., Scholtes, E.H., Zuydgeest, D., van der Kammen, R.A., Stam, J.C., Berns, A. and Collard, J.G. (1994) Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins. Cell, 77, 537-549.
Habets, G.G., van der Kammen, R.A., Jenkins, N.A., Gilbert, D.J., Copeland, N.G., Hagemeijer, A. and Collard, J.G. (1995) The invasion-inducing TIAM1 gene maps to human chromosome band 21q22 and mouse chromosome 16. Cytogenet Cell Genet, 70, 48-51.
Hall, A. (1998) Rho GTPases and the actin cytoskeleton. Science, 279, 509-514.
Hall, A. (2005) Rho GTPases and the control of cell behaviour. Biochem Soc Trans, 33, 891-895.
Hordijk, P.L., ten Klooster, J.P., van der Kammen, R.A., Michiels, F., Oomen, L.C. and Collard, J.G. (1997) Inhibition of invasion of epithelial cells by Tiam1-Rac signaling. Science, 278, 1464-1466.
Hoshino, M., Sone, M., Fukata, M., Kuroda, S., Kaibuchi, K., Nabeshima, Y. and Hama, C. (1999) Identification of the stef gene that encodes a novel guanine nucleotide exchange factor specific for Rac1. J Biol Chem, 274, 17837-17844.
Hsiang, C.Y., Wu, S.L., Chen, J.C., Lo, H.Y., Li, C.C., Chiang, S.Y., Wu, H.C. and Ho, T.Y. (2007) Acetaldehyde induces matrix metalloproteinase-9 gene expression via nuclear factor-kappaB and activator protein 1 signaling pathways in human hepatocellular carcinoma cells: Association with the invasive potential. Toxicol Lett, 171, 78-86.
Kawauchi, T., Chihama, K., Nabeshima, Y. and Hoshino, M. (2003) The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration. Embo J, 22, 4190-4201.
Leeuwen, F.N., Kain, H.E., Kammen, R.A., Michiels, F., Kranenburg, O.W. and Collard, J.G. (1997) The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. J Cell Biol, 139, 797-807.
Llovet, J.M. and Bruix, J. (2008) Molecular targeted therapies in hepatocellular carcinoma. Hepatology, 48, 1312-1327.
Makino, N., Yamato, T., Inoue, H., Furukawa, T., Abe, T., Yokoyama, T., Yatsuoka, T., Fukushige, S., Orikasa, S., Takahashi, T. and Horii, A. (2001) Isolation and characterization of the human gene homologous to the Drosophila headcase (hdc) gene in chromosome bands 6q23-q24, a region of common deletion in human pancreatic cancer. DNA Seq, 11, 547-553.
Malliri, A., Rygiel, T.P., van der Kammen, R.A., Song, J.Y., Engers, R., Hurlstone, A.F., Clevers, H. and Collard, J.G. (2005) The RAC activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumour development. J Biol Chem.
Malliri, A., Rygiel, T.P., van der Kammen, R.A., Song, J.Y., Engers, R., Hurlstone, A.F., Clevers, H. and Collard, J.G. (2006) The rac activator Tiam1 is a Wnt-responsive gene that modifies intestinal tumor development. J Biol Chem, 281, 543-548.
Malliri, A., van der Kammen, R.A., Clark, K., van der Valk, M., Michiels, F. and Collard, J.G. (2002) Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature, 417, 867-871.
Mann, C.D., Neal, C.P., Garcea, G., Manson, M.M., Dennison, A.R. and Berry, D.P. (2007) Prognostic molecular markers in hepatocellular carcinoma: a systematic review. Eur J Cancer, 43, 979-992.
Matsuo, N., Hoshino, M., Yoshizawa, M. and Nabeshima, Y. (2002) Characterization of STEF, a guanine nucleotide exchange factor for Rac1, required for neurite growth. J Biol Chem, 277, 2860-2868.
Matsuo, N., Terao, M., Nabeshima, Y. and Hoshino, M. (2003) Roles of STEF/Tiam1, guanine nucleotide exchange factors for Rac1, in regulation of growth cone morphology. Mol Cell Neurosci, 24, 69-81.
Mertens, A.E., Roovers, R.C. and Collard, J.G. (2003) Regulation of Tiam1-Rac signalling. FEBS Lett, 546, 11-16.
Michiels, F., Habets, G.G., Stam, J.C., van der Kammen, R.A. and Collard, J.G. (1995) A role for Rac in Tiam1-induced membrane ruffling and invasion. Nature, 375, 338-340.
Michiels, F., Stam, J.C., Hordijk, P.L., van der Kammen, R.A., Ruuls-Van Stalle, L., Feltkamp, C.A. and Collard, J.G. (1997) Regulated membrane localization of Tiam1, mediated by the NH2-terminal pleckstrin homology domain, is required for Rac-dependent membrane ruffling and C-Jun NH2-terminal kinase activation. J Cell Biol, 137, 387-398.
Minard, M.E., Ellis, L.M. and Gallick, G.E. (2006) Tiam1 regulates cell adhesion, migration and apoptosis in colon tumor cells. Clin Exp Metastasis, 23, 301-313.
Minard, M.E., Kim, L.S., Price, J.E. and Gallick, G.E. (2004) The role of the guanine nucleotide exchange factor Tiam1 in cellular migration, invasion, adhesion and tumor progression. Breast Cancer Res Treat, 84, 21-32.
Nakajima, S., Doi, R., Toyoda, E., Tsuji, S., Wada, M., Koizumi, M., Tulachan, S.S., Ito, D., Kami, K., Mori, T., Kawaguchi, Y., Fujimoto, K., Hosotani, R. and Imamura, M. (2004) N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res, 10, 4125-4133.
Nieman, M.T., Prudoff, R.S., Johnson, K.R. and Wheelock, M.J. (1999) N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J Cell Biol, 147, 631-644.
Nishimura, T., Yamaguchi, T., Kato, K., Yoshizawa, M., Nabeshima, Y., Ohno, S., Hoshino, M. and Kaibuchi, K. (2005) PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol, 7, 270-277.
Otsuki, Y., Tanaka, M., Yoshii, S., Kawazoe, N., Nakaya, K. and Sugimura, H. (2001) Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc Natl Acad Sci U S A, 98, 4385-4390.
Pang, R.W., Joh, J.W., Johnson, P.J., Monden, M., Pawlik, T.M. and Poon, R.T. (2008) Biology of hepatocellular carcinoma. Ann Surg Oncol, 15, 962-971.
Perrino, C., Rockman, H.A. and Chiariello, M. (2006) Targeted inhibition of phosphoinositide 3-kinase activity as a novel strategy to normalize beta-adrenergic receptor function in heart failure. Vascul Pharmacol, 45, 77-85.
Qi, Y., Huang, B., Yu, L., Wang, Q., Lan, G. and Zhang, Q. (2009) Prognostic value of Tiam1 and Rac1 overexpression in nasopharyngeal carcinoma. ORL J Otorhinolaryngol Relat Spec, 71, 163-171.
Ridley, A.J. (2006) Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol, 16, 522-529.
Rossman, K.L., Der, C.J. and Sondek, J. (2005) GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol, 6, 167-180.
Sander, E.E., ten Klooster, J.P., van Delft, S., van der Kammen, R.A. and Collard, J.G. (1999) Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol, 147, 1009-1022.
Schmidt, A. and Hall, A. (2002) Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev, 16, 1587-1609.
Seo, D.D., Lee, H.C., Kim, H.J., Min, H.J., Kim, K.M., Lim, Y.S., Chung, Y.H., Lee, Y.S., Suh, D.J., Yu, E. and Chun, S.Y. (2008) Neural cadherin overexpression is a predictive marker for early postoperative recurrence in hepatocellular carcinoma patients. J Gastroenterol Hepatol, 23, 1112-1118.
Stemmler, M.P. (2008) Cadherins in development and cancer. Mol Biosyst, 4, 835-850.
Sun, H.S., Su, I.J., Lin, Y.C., Chen, J.S. and Fang, S.Y. (2003) A 2.6 Mb interval on chromosome 6q25.2-q25.3 is commonly deleted in human nasal natural killer/T-cell lymphoma. Br J Haematol, 122, 590-599.
Tolias, K.F., Bikoff, J.B., Burette, A., Paradis, S., Harrar, D., Tavazoie, S., Weinberg, R.J. and Greenberg, M.E. (2005) The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron, 45, 525-538.
Uhlenbrock, K., Eberth, A., Herbrand, U., Daryab, N., Stege, P., Meier, F., Friedl, P., Collard, J.G. and Ahmadian, M.R. (2004) The RacGEF Tiam1 inhibits migration and invasion of metastatic melanoma via a novel adhesive mechanism. J Cell Sci, 117, 4863-4871.
Van Aelst, L. and D'Souza-Schorey, C. (1997) Rho GTPases and signaling networks. Genes Dev, 11, 2295-2322.
van Leeuwen, F.N., Kain, H.E., Kammen, R.A., Michiels, F., Kranenburg, O.W. and Collard, J.G. (1997) The guanine nucleotide exchange factor Tiam1 affects neuronal morphology; opposing roles for the small GTPases Rac and Rho. J Cell Biol, 139, 797-807.
van Leeuwen, F.N., van der Kammen, R.A., Habets, G.G. and Collard, J.G. (1995) Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells. Oncogene, 11, 2215-2221.
Villalonga, P. and Ridley, A.J. (2006) Rho GTPases and cell cycle control. Growth Factors, 24, 159-164.
Whitehead, I.P., Campbell, S., Rossman, K.L. and Der, C.J. (1997) Dbl family proteins. Biochim Biophys Acta, 1332, F1-23.
Yao, D.F., Dong, Z.Z. and Yao, M. (2007) Specific molecular markers in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int, 6, 241-247.
Yoshizawa, M., Hoshino, M., Sone, M. and Nabeshima, Y. (2002) Expression of stef, an activator of Rac1, correlates with the stages of neuronal morphological development in the mouse brain. Mech Dev, 113, 65-68.
Zondag, G.C., Evers, E.E., ten Klooster, J.P., Janssen, L., van der Kammen, R.A. and Collard, J.G. (2000) Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J Cell Biol, 149, 775-782.
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