綠茶表沒食子酸酯型唲茶素酸酯和第一型內皮素對於脂肪細胞中細胞激素訊息抑制物基因的交互作用

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研究生：	張欣蕙 Hsin-huei Chang
論文名稱：	綠茶表沒食子酸酯型唲茶素酸酯和第一型內皮素對於脂肪細胞中細胞激素訊息抑制物基因的交互作用 Green tea epigallocatechin gallate and endothelin-1 interact on suppressors of cytokine signaling genes in 3T3-L1 adipocytes
指導教授：	高永旭 Yung-hsi Kao
口試委員:
學位類別：	博士 Doctor
系所名稱：	生醫理工學院 - 生命科學系 Department of Life Science
論文出版年：	2014
畢業學年度：	102
語文別：	英文
論文頁數：	174
中文關鍵詞：	表沒食子酸酯型唲茶素酸酯、第一型內皮素、細胞激素訊息抑制物、脂肪細胞
外文關鍵詞：	Epigallocatechin gallate, Endothelin-1, Suppressors of cytokine signaling, Adipocyte
相關次數：	點閱：15 下載：0
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第一型內皮素(endothelin-1)、細胞激素訊息抑制物-3 (suppressor of cytokine signaling-3; SOCS-3)和表沒食子酸酯型唲茶素酸酯(epigallocatechin gallate; EGCG)皆為調節脂質代謝與葡萄糖抗性的重要物質。然而至今仍未有清晰的證據顯示ET-1、SOCS-3和EGCG間的調節關係。因此，本論文欲探討ET-1對於SOCS-3的調節作用，並且更深入的了解EGCG是否會影響ET-1對於SOCS-3的作用。
在第一章中發現，ET-1會增加SOCS-1, -2, -3, -4, -5和-6的mRNA，但此作用並不會在SOCS-7和CIS-1中觀察到。ET-1對於SOCS-3的促進作用需要新RNA的合成，並且具有細胞特異性(cell-type specific)。ET-1對於SOCS-3 mRNA和蛋白質的促進作用是透過ERK、JNK、PI3K和JAK路徑。
第二章顯示，在3T3-L1脂肪細胞中，EGCG抑制ET-1所促進的SOCS-3基因表現是透過67LR和AMPK路徑。EGCG亦會抑制被ET-1所促進的SOCS-1、SOCS-2、SOCS-3、SOCS-4、SOCS-5和SOCS-6的mRNA表現，但此現象並沒有在SOCS-7和CIS-1中觀察到。EGCG也會抑制ET-1所增加的不同訊息蛋白的磷酸化表現，例如ERKs、p38、JNKs、cJUN和JAK2，其中也包含EGCG作用較不明顯的STAT-3蛋白。
在第三章，確立了從老鼠初代脂肪細胞和繼代脂肪細胞分離出的67LR為885鹼基對 (bp)與295個胺基酸，且其與大鼠和人類的基因序列相似性分別為96%和89%。67LR會依據不同組織與不同生長狀態而有不同的表現情形。67LR免疫血清的處理，阻斷了EGCG對於3T3-L1前脂肪細的生長抑制作用，此結果證實了EGCG抑制細胞生長作用須透過67LR作用。
於第四章中，成功將人類與老鼠的全長(67LR1-295)及不同缺失片段 (67LR1-200, 67LR1-150, 67LR1-100 and 67LR1-55) 67LR建構成Flag融合蛋白表現質體，並且進一步篩選出KB和MCF-7穩定表現細胞株。生長實驗指出，67LR的增生作用會依據癌細胞種類的不同與67LR蛋白的不同區域而有所不同。在MCF-7和KB的不同型67LR表現細胞株中處理EGCG，結果顯示67LR的151-200胺基酸位置對於67LR調節EGCG的抑制增生作用是很重要的。
第五章中，成功得到一隻帶有Rpsa-異型合子的老鼠。未來須得到Rpsa-/-同型合子的老鼠供研究所用。
我們歸納出ET-1會透過ETAR、ERK、JNK、JAK和PI3K路徑作用於特定的SOCS家族成員，但不包含ETBR路徑。而EGCG的抗ET-1 作用則是透過67LR和AMPK路徑。如同67LR被發現是EGCG的接受器、SOCS蛋白為胰島素訊息的抑制物，本篇論文的結果或許能有助於解釋EGCG和ET-1對於脂肪細胞功能和胰島素訊息的交互作用機制。

Endothelin (ET)-1, suppressor of cytokine signaling (SOCS)-3 and epigallocatechin gallate (EGCG) are important to regulate the lipid metabolism and insulin resistance, respectively. However, no clear evidence is showed the relationship among ET-1, SOCS-3 and EGCG. This dissertation was designed to understand the effect of ET-1 on modulating the SOCS-3 gene and further investigate whether EGCG regulated the effect of ET-1 on SOCS-3 gene.
Chapter One indicated that ET-1 upregulated the expression of SOCS-1, SOCS-2, SOCS-3, SOCS-4, SOCS-5, and SOCS-6 mRNAs, but not SOCS-7 or cytokine-inducible SH2-containing protein (CIS)-1 mRNAs. The ET-1 stimulation of SOCS-3 mRNA expression required new RNA synthesis and was cell-type specific. The stimulatory effects of ET-1 on SOCS-3 mRNA and protein expression were mediated through the ERK, JNK, PI3K, and JAK2 pathways.
Chapter Two showed that EGCG suppressed the ET-1-induced expression of the SOCS-3 gene in 3T3-L1 adipocytes through the 67LR and AMPK pathways. EGCG also suppressed the ET-1-stimulated expression of SOCS-1, -2, -4, -5 and -6 mRNAs, but not SOCS-7 or CIS-1 mRNAs. EGCG inhibited the ET-1-increased phosphorylation of different ET-1 signaling proteins, such as ERKs, p38, JNK, cJUN, AKT, JAK, and, to a lesser extent, STAT-3 proteins.
Chapter Three indicated that 67LR gene was isolated and sequenced with 885 bp and 295 amino acid (aa) from murine primary and secondary adipocytes and it had the 96% and 89% homology of nucleotide sequence to rat and human. The 67LR expression depended on tissue types and growth status. Treatment with 67LR antiserum blocked the inhibitory effect of EGCG on cell number in 3T3-L1 preadipocytes, suggesting the 67LR-dependent effect.
Chapter Four showed that different plasmids for recombinant full-length (67LR1-295) and truncated forms (67LR1-200, 67LR1-150, 67LR1-100 and 67LR1-55) of human and mouse 67LR were constructed with a Flag tag and stably cloned in KB oral cancer cells and MCF-7 breast cancer cells were established. Growth experiments indicated mitogenic effect of 67LR on cancer cells varies with cell types and different domains of the 67LR protein. Different forms of 67LR stably cloned MCF-7 and KB cells treated with EGCG showed that amino acid residues of the 67LR from 151-200 are important for modulating the antimitogenic effects of EGCG on MCF-7 and KB cancer cells.
Chapter Five was successful to generate one heterozygous 67LR gene (also called Rpsa-/flox alleles), the mice with Rpsa-/- alleles would be needed for a further study.
We conclude that ET-1 acts particular types of SOCS family members through the ETAR, ERK, JNK, JAK and PI3K but not ETBR pathways. The anti-ET-1 signaling effect of EGCG is mediated by 67LR and AMPK pathways. As the 67LR was discovered as an EGCG receptor and as the SOCS proteins were reported as an insulin signaling inhibitor, results of this dissertation could help explain the mechanism of how EGCG and ET-1 interacts on adipocyte functions and insulin signaling.

Chinese Abstract                                         i
English Abstract                                         iii
Declaration                                              v
Acknowledgments                                          vi
Table of Contents                                        vii
List of Figures                                          xi
List of Tables                                           xiv
Abbreviations                                            xv

1.Chapter One. The effect of endothelin-1 on the expression of suppressors of cytokine signaling genes               1
 1-1.    Introduction                                    3
 1-2.    Materials and Methods                           6
   1-2.1. Chemical reagents                              6
   1-2.2. Cell culture                                   6
   1-2.3. Real-time and reverse-transcriptase polymerase chain reaction (RT-PCR) for SOCS mRNAs                   7
   1-2.4. Western blot analysis                          9
   1-2.5. Statistical analysis                           9
 1-3. Results                                            10
   1-3.1. Effects of ET-1 on SOCS-3 mRNA expression      10
   1-3.2.ET-1 stimulates expression of SOCS family genes 10
   1-3.3 Effect of ET-1 on SOCS-3 mRNA expression depends on the type A ET receptor                                11
   1-3.4. ET-1-induced upregulation of SOCS-3 mRNA expression depends on the MAPK, PI3K and JAK pathways    11
   1-3.5. ET-1 effects are cell type specific            12
   1-3.6. The stimulatory effect of ET-1 on SOCS-3 mRNA expression depends on the different locations of adipose tissues in mice                                          13
   1-3.7. ET-1-induced upregulation of SOCS-3 protein expression depends on the ERK MAPK, PI3K, JNK and JAK pathways                                                 13
 1-4. Discussion                                         15
 1-5. Conclusions                                        19
 1-6. References                                         20

2. Chapter Two. Epigallocatechin gallate regulates the effect of  endothelin-1 on the expression of suppressor of cytokine signaling-3 gene in 3T3-L1 adipocytes           24
 2-1.   Introduction                                     26
 2-2. Materials and Methods                              29
   2-2.1. Chemical reagents                              29
   2-2.2. Cell culture                                   29
   2-2.3. Real-time and reverse-transcriptase polymerase chain reaction (RT-PCR) for SOCS mRNAs                   30
   2-2.4. Western blot analysis                          31
   2-2.5. Statistical analysis                           31
 2-3. Results and Discussion                             33
   2-3.1. EGCG suppressed ET-1-stimulated expression of SOCS-3 and other SOCS genes                              33
   2-3.2. EGCG changed ET-1-induced phosphorylation of MAPK molecules                                                34
   2-3.3. EGCG changed ET-1-induced phosphorylation of JAK2/STAT-3 and PI3K/AKT signaling proteins              36
   2-3.4. EGCG repressed the ET-1-stimulated expression of SOCS-3 mRNA through the 67LR pathway                     37
   2-3.5. AMPK mediated the effect of EGCG on the ET-1-induced increases in SOCS-3 gene expression              38
   2-3.6. EGCG altered ET-1-induced changes in levels of different SOCS member proteins                           39
 2-4. Conclusions                                        41
 2-5. References                                         42

3. Chapter Three. The 67-kilodalton laminin receptor in adipose tissue and its roles in mediating actions of epigallocatechin gallate on 3T3-L1 preadipocytes and adipocytes                                               45
 3-1. Introduction                                       48
 3-2. Materials and Methods                              51
   3-2.1. Chemical reagents                              51
   3-2.2. Cell culture                                   51
   3-2.3. Growth inhibition experiments                  52
   3-2.4. RNA extraction, oligonucleotide primers and RT-PCR                                                      52
   3-2.5. Western blot analysis                          53
   3-2.6. Statistical analysis                           54
 3-3. Resulats and Discussion                            55
   3-3.1. EGCG receptor expressed in primary and secondary fat cells                                                55
   3-3.2. Tissue-specific distribution of 67LR           55
   3-3.3. Expression of the 67LR mRNA and protein changed during growth and differentiation of 3T3-L1 preadipocytes to adipocytes                                            56
   3-3.4. The 67LR antibody                              57
   3-3.5. The 67LR antibody blocked the effects of EGCG  58 
 3-4. Conclusions                                        60
 3-5. References                                         61

4. Chapter Four. Constructs of the full-length and truncated forms of 67-kilodalton laminin receptor and their mediatory effects of epigallocatechin gallate on the mitogenesis of KB and MCF-7 cancer cells                 64
 4-1. Introduction                                       66
 4-2. Materials and Methods                              68
   4-2.1. Chemical reagents                              68
   4-2.2. Cell culture                                   68
   4-2.3. 67LR plasmids construct                        69
   4-2.4. Cell transfection and overexpression experiments                                              70
   4-2.5. Growth inhibition experiments                  70
   4-2.6. RNA extraction, oligonucleotide primers and RT-PCR                                                      71
   4-2.7. Western blot analysis                          72
   4.2.8. Statistical analysis                           72
 4-3. Results and Discussion                             73
   4-3.1. Construction of mouse and human 67LR           73
   4-3.2. Stable clones of human MCF-7 breast cancer cells and human KB oral cancer cells with overexpression of different sizes of human 67LR                            74 
   4-3.3. Overexpression of the normal and truncated 67LR modulated the growth of polyclonal MCF-7 and KB cancer cells                                                    75
   4-3.4. Overexpression of the normal and truncated 67LR mediated the inhibitory effect of EGCG on growth of human MCF-7 and KB cancer cells                                76
   4-3.5. The mouse 67LR involved in the regulation of EGCG on cell growth                                           78 
 4-4. Conclusions                                        79
 4-5. References                                         80

5. Chapter Five. Development of 67 kilodalton laminin receptor – knockout mice                                 82
 5-1. Introduction                                       84
 5-2. Materials and Methods                              86
   5-2.1. Chemical reagents                              86
   5.2.2. BAC clone DNA preparation                      86
   5-2.3. The probes of southern blot assay preparation  86
   5-2.4. Extraction of mice tail DNA                    87
   5-2.5. Genotyping of mice tail DNA                    87
 5-3. Results and Discussion                             88
   5-3.1. Construction of a targeting plasmid            88
   5-3.2. Confirmation of the targeted ES cells          88
   5-3.3. Cre recombined targeted ES cells               89
   5-3.4. Flpe recombined targeted ES cells              90
   5-3.5. Generation of conventional 67LR-knockout mice with Cre-recombined chimera                              91 
   5-3.6. Generation of conventional 67LR-knockout mice - PrmCre mice                                              92
   5-3.7. Generation of conventional and conditional 67LR-knockout mice with Flpe recombined chimera               94
 5-4. Conclusions                                        96
 5-5. References                                         97

Figures 1-42                                             98
Tables 1-4                                               158
Appendix 1. Cell viability assay                         164
Appendix 2. A respective dissociation curve for SOCS-3 and GAPDH indicates the specificity of real-time PCR analysis165
Appendix 3. A parallelism of titration curves for SOCS-3 and GAPDH indicates the respective efficiency of their real-time PCR analysis                                        166
Appendix 4. A respective end-point RT-PCR analysis for SOCS-3 and GAPDH indicates the specificity and exponential change                                                   167
Appendix 5. Actinomycin D pretreatment blocked the increased SOCS-3 protein levels which induced by 4-h treatment with ET-1                                      168
Appendix 6. Human 67LR overexpressed by yeast which contain His-fusion h67LR                                         169
Appendix 7. Southern blot of EcoRV-digested genomic DNA for selection of targeted ES cells                           170
Appendix 8. PCR analysis of 5’loxP site in the targeted ES cells                                                    171
Appendix 9. Cre recombinase-excised targeted ES cells analyzed by PCR amplification and restriction enzyme     172
Appendix 10. Flpe recombinase-excised targeted ES cells analyzed by PCR amplification and restriction enzyme     173
Appendix 11. Genotyping of F1 progeny of Flpe-recombined chimera mice by TMCC                                     174

                                

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Chapter 2:
Juan, C.C., et al., Endothelin-1 induces lipolysis in 3T3-L1 adipocytes. American Journal of Physiology - Endocrinology And Metabolism, 2005. 288(6): p. E1146-E1152.
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3. Juan, C.C., et al., Endothelin-1 Regulates Adiponectin Gene Expression and Secretion in 3T3-L1 Adipocytes via Distinct Signaling Pathways. Endocrinology, 2007. 148(4): p. 1835-1842.
4. Zhong, Q., et al., Endothelin-1 inhibits resistin secretion in 3T3-L1 adipocytes. Biochemical and Biophysical Research Communications, 2002. 296(2): p. 383-387.
5. Usui, I., et al., G Protein-Coupled Receptor Kinase 2 Mediates Endothelin-1-Induced Insulin Resistance via the Inhibition of Both Gαq/11 and Insulin Receptor Substrate-1 Pathways in 3T3-L1 Adipocytes. Molecular Endocrinology, 2005. 19(11): p. 2760-2768.
6. Spinella, F., et al., Green tea polyphenol epigallocatechin-3-gallate inhibits the endothelin axis and downstream signaling pathways in ovarian carcinoma. Molecular Cancer Therapeutics, 2006. 5(6): p. 1483-1492.
7. Reiter, C.E.N., J.A. Kim, and M.J. Quon, Green Tea Polyphenol Epigallocatechin Gallate Reduces Endothelin-1 Expression and Secretion in Vascular Endothelial Cells: Roles for AMP-Activated Protein Kinase, Akt, and FOXO1. Endocrinology, 2010. 151(1): p. 103-114.
8. Lin, T. S., Signaling mechanism of green tea (-)-epigallocatechin gallate inhibits the effects of endothelin-1 on 3T3-L1 adipocyte glucose uptake. Thesis of Department of Life Science, National Central University University central, 2013: p. 63.
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10. Wang, C.T., et al., The effects of green tea (–)-epigallocatechin-3-gallate on reactive oxygen species in 3T3-L1 preadipocytes and adipocytes depend on the glutathione and 67 kDa laminin receptor pathways. Molecular Nutrition & Food Research, 2009. 53(3): p. 349-360.
11. Ku, H.C., et al., Green tea (−)-epigallocatechin gallate inhibits insulin stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor pathway. American Journal of Physiology-Cell Physiology, 2009. 297(1): p. C121-C132.
12. Hsieh, C.F., et al., Green tea epigallocatechin gallate inhibits insulin stimulation of adipocyte glucose uptake via the 67-kilodalton laminin receptor and AMP-activated protein kinase pathways. Planta medica, 2010. 76(15): p. 1694-1698.
13. Qu, Y., S. Dang, and P. Hou, Gene methylation in gastric cancer. Clinica Chimica Acta, 2013. 424(0): p. 53-65.
14. Lee, I.T., et al., Protective effects of (−)-epigallocatechin-3-gallate against TNF-α-induced lung inflammation via ROS-dependent ICAM-1 inhibition. The Journal of Nutritional Biochemistry, 2013. 24(1): p. 124-136.
15. Steppan, C.M., et al., Activation of SOCS-3 by Resistin. Molecular and Cellular Biology, 2005. 25(4): p. 1569-1575.
16. Ueki, K., T. Kondo, and C.R. Kahn, Suppressor of Cytokine Signaling 1 (SOCS-1) and SOCS-3 Cause Insulin Resistance through Inhibition of Tyrosine Phosphorylation of Insulin Receptor Substrate Proteins by Discrete Mechanisms. Molecular and Cellular Biology, 2004. 24(12): p. 5434-5446.
17. Jiao, Y., et al., CISH has no non-redundant functions in glucose homeostasis or beta cell proliferation during pregnancy in mice. Diabetologia, 2013. 56(11): p. 2435-2445.
18. Tellechea, M.L., et al., Common variants in SOCS7 gene predict obesity, disturbances in lipid metabolism and insulin resistance. Nutrition, Metabolism and Cardiovascular Diseases, 2013. 23(5): p. 424-431.
19. Koike, K., Hepatitis C as a metabolic disease: Implication for the pathogenesis of NASH. Hepatology research, 2005. 33(2): p. 145-150.
20. Sae-Tan, S., K.A. Grove, and J.D. Lambert, Weight control and prevention of metabolic syndrome by green tea. Pharmacological Research, 2011. 64(2): p. 146-154.
21. Kao, Y.H., et al., Tea, obesity, and diabetes. Molecular Nutrition & Food Research, 2006. 50(2): p. 188-210.
22. Fong, J.C., et al., Endothelin-1 increases glucose transporter glut1 mRNA accumulation in 3T3-L1 adipocytes by a mitogen-activated protein kinase-dependent pathway. Cellular Signalling, 2001. 13(7): p. 491-497.
23. Chang, H.H., et al., Endothelin-1 stimulates suppressor of cytokine signaling-3 gene expression in adipocytes. General and Comparative Endocrinology, 2012. 178(3): p. 450-458.
24. Wu-Wong, J.R., et al., Endothelin Stimulates Glucose Uptake and GLUT4 Translocation via Activation of Endothelin ETA Receptor in 3T3-L1 Adipocytes. Journal of Biological Chemistry, 1999. 274(12): p. 8103-8110.
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26. Lam, K.K.W., et al., Glycodelin-A Protein Interacts with Siglec-6 Protein to Suppress Trophoblast Invasiveness by Down-regulating Extracellular Signal-regulated Kinase (ERK)/cJUN Signaling Pathway. Journal of Biological Chemistry, 2011. 286(43): p. 37118-37127.
27. Musti, A.M., M. Treier, and D. Bohmann, Reduced Ubiquitin-Dependent Degradation of cJUN After Phosphorylation by MAP Kinases. Science, 1997. 275(5298): p. 400-402.
28. Treisman, R., Regulation of transcription by MAP kinase cascades. Current Opinion in Cell Biology, 1996. 8(2): p. 205-215.
29. Tokuda, H., et al., (−)-Epigallocatechin gallate suppresses endothelin-1-induced interleukin-6 synthesis in osteoblasts: Inhibition of p44/p42 MAP kinase activation. FEBS Letters, 2007. 581(7): p. 1311-1316.
30. Choi, J. S., et al., Dietary Flavonoids Differentially Reduce Oxidized LDL-Induced Apoptosis in Human Endothelial Cells: Role of MAPK- and JAK/STAT-Signaling. The Journal of Nutrition, 2008. 138(6): p. 983-990.
31. Menegazzi, M., et al., Anti-interferon-g action of epigallocatechin-3-gallate mediated by specific inhibition of STAT1 activation. The FASEB Journal, 2001.
32. Menegazzi, M., et al., Direct interaction of natural and synthetic catechins with Signal Transducer Activator of Transcription-1 affects both its phosphorylation and activity. FEBS Journal, 2013: p. n/a-n/a.
33. Waltner-Law, M.E., et al., Epigallocatechin Gallate, a Constituent of Green Tea, Represses Hepatic Glucose Production. Journal of Biological Chemistry, 2002. 277(38): p. 34933-34940.
34. Babu, P.V.A., D. Liu, and E.R. Gilbert, Recent advances in understanding the anti-diabetic actions of dietary flavonoids. The Journal of Nutritional Biochemistry, 2013. 24(11): p. 1777-1789.
35. Javadov, S., et al., Anti-hypertrophic effect of NHE-1 inhibition involves GSK-3β-dependent attenuation of mitochondrial dysfunction. Journal of Molecular and Cellular Cardiology, 2009. 46(6): p. 998-1007.
36. Fujioka, D., et al., Role of adiponectin receptors in endothelin-induced cellular hypertrophy in cultured cardiomyocytes and their expression in infarcted heart. American Journal of Physiology - Heart and Circulatory Physiology, 2006. 290(6): p. H2409-H2416.
Chapter 3:
1. Singh, B.N., Shankar S., and Srivastava R.K., Green tea catechin, epigallocatechin-3-gallate (EGCG): Mechanisms, perspectives and clinical applications. Biochemical Pharmacology, 2011. 82(12): p. 1807-1821.
2. Liao, S., Kao Y.H., and Hiipakka R.A., Green tea: biochemical and biological basis for health benefits. Vitamins & Hormones, 2001. 62: p. 1-94.
3. Yang, C.S. and Wang Z.Y., Tea and Cancer. Journal of the National Cancer Institute, 1993. 85(13): p. 1038-1049.
4. Haqqi, T.M., et al., Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea. Proceedings of the National Academy of Sciences, 1999. 96(8): p. 4524-4529.
5. Mandel, S. and Youdim M.B.H., Catechin polyphenols: neurodegeneration and neuroprotection in neurodegenerative diseases. Free Radical Biology and Medicine, 2004. 37(3): p. 304-317.
6. Rezai-Zadeh, K., et al., Green Tea Epigallocatechin-3-Gallate (EGCG) Modulates Amyloid Precursor Protein Cleavage and Reduces Cerebral Amyloidosis in Alzheimer Transgenic Mice. The Journal of Neuroscience, 2005. 25(38): p. 8807-8814.
7. Song, E.K., Hur H., and Han M.K., Epigallocatechin gallate prevents autoimmune diabetes induced by multiple low doses of streptozotocin in mice. Archives of pharmacal research, 2003. 26(7): p. 559-563.
8. Nagao, T., et al., Ingestion of a tea rich in catechins leads to a reduction in body fat and malondialdehyde-modified LDL in men. The American Journal of Clinical Nutrition, 2005. 81(1): p. 122-129..
9. Kao, Y.H., Hiipakka R.A., and Liao S., Modulation of Endocrine Systems and Food Intake by Green Tea Epigallocatechin Gallate. Endocrinology, 2000. 141(3): p. 980-987.
10. Dulloo, A., et al., Green tea and thermogenesis: interactions between catechin-polyphenols, caffeine and sympathetic activity. International journal of obesity, 2000. 24(2): p. 252-258.
11. Lin, J.K. and Lin-Shiau S.Y., Mechanisms of hypolipidemic and anti-obesity effects of tea and tea polyphenols. Molecular Nutrition & Food Research, 2006. 50(2): p. 211-217.
12. Ahmad, N. and Mukhtar H., Green tea polyphenols and cancer: biologic mechanisms and practical implications. Nutrition reviews, 1999. 57(3): p. 78-83.
13. Weinreb, O., S. Mandel, and Youdim M.B.H., cDNA gene expression profile homology of antioxidants and their antiapoptotic and proapoptotic activities in human neuroblastoma cells. The FASEB Journal, 2003.
14. Kao, Y.H., et al., Tea, obesity, and diabetes. Molecular Nutrition & Food Research, 2006. 50(2): p. 188-210.
15. Liu, H.S., et al., Inhibitory effect of green tea (−)-epigallocatechin gallate on resistin gene expression in 3T3-L1 adipocytes depends on the ERK pathway. American Journal of Physiology - Endocrinology and Metabolism, 2006: p. E273-E281.
16. Wolfram, S., Wang Y., and Thielecke F., Anti‐obesity effects of green tea: From bedside to bench. Molecular Nutrition & Food Research, 2006. 50(2): p. 176-187.
17. Crespy, V. and Williamson G., A Review of the Health Effects of Green Tea Catechins in In Vivo Animal Models. The Journal of Nutrition, 2004. 134(12): p. 3431S-3440S.
18. Wang, C.T., et al., The effects of green tea (–)-epigallocatechin-3-gallate on reactive oxygen species in 3T3-L1 preadipocytes and adipocytes depend on the glutathione and 67 kDa laminin receptor pathways. Molecular Nutrition & Food Research, 2009. 53(3): p. 349-360.
19. Tachibana, H., et al., A receptor for green tea polyphenol EGCG. Nat Struct Mol Biol, 2004. 11(4): p. 380-381.
20. Suzuki, Y. and Isemura M., Inhibitory effect of epigallocatechin gallate on adhesion of murine melanoma cells to laminin. Cancer Letters, 2001. 173(1): p. 15-20.
21. Umeda, D., H. Tachibana, and Yamada K., Epigallocatechin-3-O-gallate disrupts stress fibers and the contractile ring by reducing myosin regulatory light chain phosphorylation mediated through the target molecule 67 kDa laminin receptor. Biochemical and Biophysical Research Communications, 2005. 333(2): p. 628-635.
22. Givant-Horwitz, V., Davidson B., and Reich R., Laminin-Induced Signaling in Tumor Cells: The Role of the Mr 67,000 Laminin Receptor. Cancer Research, 2004. 64(10): p. 3572-3579.
23. Mecham, R.P., Receptors for laminin on mammalian cells. The FASEB Journal, 1991. 5(11): p. 2538-46.
24. Ardini, E., et al., The 67-kDa laminin receptor originated from a ribosomal protein that acquired a dual function during evolution. Molecular Biology and Evolution, 1998. 15(8): p. 1017-1025.
25. Romanov, V.I., et al., Protein Synthesis Is Required for Laminin-Induced Expression of the 67-kDa Laminin Receptor and Its 37-kDa Precursor. Biochemical and Biophysical Research Communications, 1995. 208(2): p. 637-643.
26. Rao, C., et al., Evidence for a precursor of the high-affinity metastasis-associated murine laminin receptor. Biochemistry, 1989. 28(18): p. 7476-7486.
27. Landowski, T., Dratz E., and Starkey J., Studies of the structure of the metastasis-associated 67 kDa laminin binding protein: fatty acid acylation and evidence supporting dimerization of the 32 kDa gene product to form the mature protein. Biochemistry, 1995. 34(35): p. 11276-11287.
28. Niimi, T., et al., Differentiation-dependent expression of laminin-8 (α4β1γ1) mRNAs in mouse 3T3-L1 adipocytes. Matrix Biology, 1997. 16(4): p. 223-230.
29. Burton, G.R., et al., Microarray analysis of differentiation-specific gene expression during 3T3-L1 adipogenesis. Gene, 2004. 329(0): p. 167-185.
30. Hung, P.F., et al., Antimitogenic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the ERK and Cdk2 pathways. American Journal of Physiology - Cell Physiology, 2005. 288(5): p. C1094-C1108.
31. Chang, H.H., et al., Endothelin-1 stimulates suppressor of cytokine signaling-3 gene expression in adipocytes. General and Comparative Endocrinology, 2012. 178(3): p. 450-458.
32. Chen, Y.H., et al., 17β-Estradiol Stimulates Resistin Gene Expression in 3T3-L1 Adipocytes via the Estrogen Receptor, Extracellularly Regulated Kinase, and CCAAT/Enhancer Binding Protein-α Pathways. Endocrinology, 2006. 147(9): p. 4496-4504.
33. Jackers, P., et al., Isolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21. 3. Oncogene, 1996. 13(3): p. 495.
34. Makrides, S., et al., Nucleotide sequence for a major messenger RNA for a 40 kilodalton polypeptide that is under translational control in mouse tumor cells. Nucleic Acids Research, 1988. 16(5): p. 2349.
35. Ku, H.C., et al., Green tea (−)-epigallocatechin gallate inhibits insulin stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor pathway. American Journal of Physiology-Cell Physiology, 2009. 297(1): p. C121-C132.
36. Nelson, J., et al., The 67 kDa laminin receptor: structure, function and role in disease. Biosience Reports, 2008. 028(1): p. 33-48.
37. Hsieh, C.F., et al., Green tea epigallocatechin gallate inhibits insulin stimulation of adipocyte glucose uptake via the 67-kilodalton laminin receptor and AMP-activated protein kinase pathways. Planta medica, 2010. 76(15): p. 1694-1698.
Chapter 4:
1. Kinoshita, K., et al., LBP-p40 Binds DNA Tightly through Associations with Histones H2A, H2B, and H4. Biochemical and Biophysical Research Communications, 1998. 253(2): p. 277-282.
2. Tachibana, H., et al., A receptor for green tea polyphenol EGCG. Nat Struct Mol Biol, 2004. 11(4): p. 380-381.
3. Gauczynski, S., et al., The 37-kDa/67-kDa laminin receptor acts as the cell-surface receptor for the cellular prion protein. EMBO J, 2001. 20(21): p. 5863-5875.
4. Menard, S., et al., New insights into the metastasis‐associated 67 kD laminin receptor. Journal of Cellular Biochemistry, 1997. 67(2): p. 155-165.
5. Nelson, J., et al., The 67 kDa laminin receptor: structure, function and role in disease. Biosience Reports, 2008. 028(1): p. 33-48.
6. Kawahara, E., et al., Inhibitory effects of adhesion oligopeptides on the invasion of squamous carcinoma cells with special reference to implication of αv integrins. Journal of cancer research and clinical oncology, 1995. 121(3): p. 133-140.
7. Jackers, P., et al., Isolation from a multigene family of the active human gene of the metastasis-associated multifunctional protein 37LRP/p40 at chromosome 3p21. 3. Oncogene, 1996. 13(3): p. 495.
8. Susantad, T. and Smith, D. siRNA-mediated silencing of the 37/67-kDa high affinity laminin receptor in Hep3B cells induces apoptosis. Cellular & Molecular Biology Letters, 2008. 13(3): p. 452-464.
9. Kaneda, Y., et al., The induction of apoptosis in HeLa cells by the loss of LBP-p40. Cell death and differentiation, 1998. 5(1): p. 20-28.
10. Scheiman, J., et al., Multiple Functions of the 37/67-kd Laminin Receptor Make It a Suitable Target for Novel Cancer Gene Therapy. Mol Ther, 2009. 18(1): p. 63-74.
11. Donaldson, E.A., et al., The Expression of Membrane-Associated 67-kDa Laminin Receptor (67LR) Is Modulated in Vitro by Cell-Contact Inhibition. Molecular Cell Biology Research Communications, 2000. 3(1): p. 53-59.
12. Song, T., et al., Expression of 67-kDa laminin receptor was associated with tumor progression and poor prognosis in epithelial ovarian cancer. Gynecologic Oncology, 2012. 125(2): p. 427-432.
13. Castronovo, V., Taraboletti, G. and Sobel, M. Functional domains of the 67-kDa laminin receptor precursor. Journal of Biological Chemistry, 1991. 266(30): p. 20440-20446.
14. Landowski, T., Uthayakumar, S. and Starkey, J. Control pathways of the 67 kDa laminin binding protein: surface expression and activity of a new ligand binding domain. Clinical & experimental metastasis, 1995. 13(5): p. 357-372.
15. Fujimura, Y., et al., Green tea polyphenol EGCG sensing motif on the 67-kDa laminin receptor. PLoS ONE, 2012. 7(5): p. e37942.
16. Hung, P.F., et al., Antimitogenic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the ERK and Cdk2 pathways. American Journal of Physiology - Cell Physiology, 2005. 288(5): p. C1094-C1108.
17. Fujimura, Y., et al., The 67kDa laminin receptor as a primary determinant of anti-allergic effects of O-methylated EGCG. Biochemical and Biophysical Research Communications, 2007. 364(1): p. 79-85.
18. Wu, B.T., et al., The Apoptotic Effect of Green Tea (−)-Epigallocatechin Gallate on 3T3-L1 Preadipocytes Depends on the Cdk2 Pathway. Journal of Agricultural and Food Chemistry, 2005. 53(14): p. 5695-5701.
19. Ku, H.C., et al., Green tea (−)-epigallocatechin gallate inhibits insulin stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor pathway. American Journal of Physiology-Cell Physiology, 2009. 297(1): p. C121-C132.
20. Karpatova, M., et al., Shedding of the 67‐kD laminin receptor by human cancer cells. Journal of Cellular Biochemistry, 1996. 60(2): p. 226-234.
Chapter 5:
1. Mecham, R.P., Receptors for laminin on mammalian cells. The FASEB Journal, 1991. 5(11): p. 2538-46.
2. Givant-Horwitz, V., Davidson, B. and Reich, R. Laminin-Induced Signaling in Tumor Cells: The Role of the Mr 67,000 Laminin Receptor. Cancer Research, 2004. 64(10): p. 3572-3579.
3. Auth, D. and Brawerman, G. A 33-kDa polypeptide with homology to the laminin receptor: component of translation machinery. Proceedings of the National Academy of Sciences, 1992. 89(10): p. 4368-4372.
4. Tohgo, A., et al., Structural determination and characterization of a 40 kDa protein isolated from rat 40 S ribosomal subunit. FEBS Letters, 1994. 340(1–2): p. 133-138.
5. Kinoshita, K., et al., LBP-p40 Binds DNA Tightly through Associations with Histones H2A, H2B, and H4. Biochemical and Biophysical Research Communications, 1998. 253(2): p. 277-282.
6. Takeuchi, T., et al., Flp recombinase transgenic mice of C57BL/6 strain for conditional gene targeting. Biochemical and Biophysical Research Communications, 2002. 293(3): p. 953-957.
7. Liu, P., Jenkins, N.A. and Copeland, N.G. A highly efficient recombineering-based method for generating conditional knockout mutations. Genome research, 2003. 13(3): p. 476-484.
8. Stricklett, P.K., Nelson, R.D. and Kohan, D.E. The Cre/loxP system and gene targeting in the kidney. American Journal of Physiology-Renal Physiology, 1999. 276(5): p. F651-F657.
9. Hung, P.F., et al., Antimitogenic effect of green tea (-)-epigallocatechin gallate on 3T3-L1 preadipocytes depends on the ERK and Cdk2 pathways. American Journal of Physiology - Cell Physiology, 2005. 288(5): p. C1094-C1108.
10. O’Gorman, S., et al., Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells. Proceedings of the National Academy of Sciences, 1997. 94(26): p. 14602-14607.
11. Hsieh, C.F., et al., Green tea epigallocatechin gallate inhibits insulin stimulation of adipocyte glucose uptake via the 67-kilodalton laminin receptor and AMP-activated protein kinase pathways. Planta medica, 2010. 76(15): p. 1694-1698.
12. Ku, H.C., et al., Green tea (−)-epigallocatechin gallate inhibits insulin stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor pathway. American Journal of Physiology-Cell Physiology, 2009. 297(1): p. C121-C132.

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