臺灣博碩士論文加值系統

Induction of cell cycle arrest at G1-phase by pentagalloylglucose in MCF-7.
中文摘要
Galloylglucose 是一種普遍存在於植物體內的丹寧，其結構是由一個到數個沒食子酸(gallic acid)及葡萄醣所組成。Pentagalloylglucose (5GG)是由五個沒食子酸架接在一個葡萄醣上所組成的成份。在日本傳統醫學上普遍用在胃潰瘍的治療。在之前的研究中已知5GG可以抑制多類生物屬種的NADPH dehydrogenase。我們實驗室之前的發表與實驗顯示5GG可以誘導白血球細胞HL-60的自發性凋亡；同時在低劑量時也可以抑制黑色素瘤B16的侵犯作用。本篇實驗發現5GG可藉著干擾細胞週期的進行達到抑制乳癌細胞MCF-7的生長。其機制係5GG可促使細胞內週期調控因子cyclin及CDK的抑制蛋白p27Kip的增加進以使細胞停留在G1 phase。
Inhibit epidermal growth factor induced cell growth and modulate the phosphorylation of EGFR by pentagalloylglucose in A549.
中文摘要
上皮細胞生長素 (epidermal growth factor) 在調控細胞的生長與分化上佔有很重要的角色。Pentagalloylglucose (5GG) 是由五個沒食子酸(gallic acid)及一個葡萄醣所組成的成份。在本篇實驗中發現5GG可以抑制由上皮細胞生長素所促使的細胞生長。在細胞及試管實驗皆發現5GG可以抑制上皮細胞生長素接受體(EGF receptor)經由EGF刺激所引發的磷酸化並進一步影響其下游的訊息傳遞－STAT的活化。是故，5GG所致使的細胞生長抑制機制可能是藉由此一路徑所導致。

Induction of cell cycle arrest at G1-phase by pentagalloylglucose in MCF-7.
Abstract
Galloylgluoses, which were purified from hydrolysable tannin contained in Chinese and Turkish gall, are composed of glucose and gallic acid units. It had been reported that penta-ο-galloyl-β-D-glucose (5GG) was converted from 1,2,3,6-tetragalloylglucose via β-glucogallin as a galloyl donor in pedunculate oak (Quercus robur). It had been demonstrated that 5GG is a potent and specific inhibitor of NADPH dehydrogenases. In our previous study showed that 5GG is able to induce apoptosis in HL-60 in a time- and dosage-dependent manner via the activation of caspase-3. Recently we found that 5GG was capable for perturbation of cell cycle in human breast caner cell line MCF-7. In DNA flow cytometric analysis showed that 5GG exhibited the ability of blocking cell cycle progression in G1 phase. Over 24 hours exposure to 5GG, the related amount of several G1 phase-related cyclins and cyclin-dependent kinase had no obvious difference. However, the activity of cyclin E/CDK2 was significantly decreased in dosage- and time-dependent manner. And the activity of cyclin D/CDK4 was also inhibited when the cells were released from serum-starved synchronization. p27Kip and p21Cip, the regulators of cyclin/CDK complexes in G1-phase, were also altered. The level of p27Kip was gradually increased, but p21Cip, in contrast to p27Kip, was decreased in a time-dependent manner. These results suggested that the function of 5GG to arrest the cell cycle progression was mediated at least by interference in cyclin D/CDK4 and cyclin E/CDK2 activity or induction of CDK inhibitor p27Kip.
Inhibit epidermal growth factor induced cell growth and modulate the phosphorylation of EGFR by pentagalloylglucose in A549.
Abstract
Epidermal growth factor plays an important role in the regulation of cell growth and differentiation by conduction of a variety of signaling pathways in many cells. 5GG (penta-ο-galloyl-β-D-glucose), which were purified from hydrolysable tannin and composed of glucose and gallic acid units, shows the ability to inhibit the EGF-stimulated poliferation of non-small cell lung cancer A549. In vivo and in vitro assay demonstrated that 5GG could inhibit the tyrosine kinase activity of EGFR at 5-10 μM, and then dramatically interfere the down-stream signaling pathway－STATs, rather then MAPKs. Upon the activation of ERK and JNK by EGF, 5GG-pretreatment were barely interfere the activation of ERK and JNK at 10 μM. The significant inhibition of active status of ERK and JNK were conducted at the concentration of 20 to 30 μM of 5GG. And stimulation by EGF or both 5GG and EGF didn’t activate p38 MAPK. Inhibition of tyrosyl-phosphorylation of EGFR stimulated by EGF resulted in the reduce of activated status STAT1 and STAT3 compared with active STATs stimulated by EGF. The effectively concentration of 5GG for the inhibition of activations of STAT1 and STAT3 is approximately at 5-10 μM. EMSA assay conducted by nuclear fraction extracted from 5GG-treated cells also showed that the reduced active STATs actually abrogated the binding to SIE element (c-cis-inducible element), which is identified as a STAT binding element, and exist in the promoter region of many genes, such as c-fos. The amount of c-fos mRNA was actually reduced while 5GG treatment prior EGF stimulation. Thus, 5GG may be a potent compound to inhibit the poliferation of tumor cells promoted by EGF with overexpression of EGFR.

Table of contents
Part IInduction of cell cycle arrest at G1-phase by pentagalloylglucose in MCF-7.
Abstract in ChineseAbstractIntroductionMaterials and methodsResultsDiscussionReferencesFigures and tables2349172328
Part IIInhibit epidermal growth factor induced cell growth and modulate the phosphorylation of EGFR by pentagalloylglucose in A549.
Abstract in ChineseAbstractIntroductionMaterials and methodsResultsDiscussionReferencesFigures and tables33343540455054

References
Baeuerle P. A. (1991) The inducible transcruption factor NF-Kappa B：regulation by distinct protein subunits. Biochem. Biophy. Acta. 1072:63-80
Baeuerle P. A., and Baltimore D. (1988) I-kappa B：a specific inhibitor of NF-κB transcription factor. Science 242:540-6
Blain S. W., E. Montalvo, and J. Massagué (1997) Differential interaction of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2 and cyclin D2-Cdk4. JBC. 272:25863-72
Boland M. P., Foster S. J., and Oneill L. AJ. (1997) Daurnorubicin activates NF-kappa B and induces I-kappa B-dependent gene expression in HL-60 promyelocytic and Jurkat T lymphoma cells. JBC. 272:12952-60
C. J. Sherr, and James M. Roberts (1999) CDK inhibitors：positive and negative regulators of G1 phase progression. Genes＆Development 13：1501-12
Chen J., P. K. Jackson, M. W. Kerschner, and A. Dutta (1995) Separate domains of p21 involved in the inhibition of kinase and PCNA. Nature 374:386-88
Chen J., P. Saha, S. Kornbluth, B. D. Dynlacht, and A. Dutta (1996) Cyclin-binding motifs are essential for the function of p21cip1. Mol. Cell. Biol. 16:4673-82
Chin Y. E., Fu X. Y., et al. (1996) Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21Waf1/Cip1 mediated by STAT1. Science 272:719-22
Das K. C., and White C. W. (1997) Activation of NF-kappa B by antineoplastic agents. Roles of protein kinase C. JBC. 272:14914-20
Donjerkovic D., and Scott D. W. (2000) Regulation of the G1 phase of the mammalian cell cycle. Cell Research. 10(1):1-16,
E. Ito, K. Maruyama, et al. (1999) Two short sequences have positive effects on the human p27Kip1 gene transcription. Gene 228:93-100
Elledge S. J., Richman R., Hall F. L., et al. (1992) CDK2 encodes a 33-kDa cyclin A- associated protein kinase and is expressed before CDC2 in the cell cycle. Proc. Natl. Acad. Sci. 89：2907-11
Ezhersky S. A., Nagahara A. M., Vocero-Akbani D. R., Gius M. C., and Wei S. F. Dowdy (1997) Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexess result in active pRb. Proc. Natl. Acad. Sci. 94：10699-704
Fesquet D., Labbe C. J., Deramcourt J., et al. (1993) The MO15 gene encodes the catalytic subunit of a protein kinase that activates Cdc2 and other cyclin-dependent kiase (CDKs) through phosphorylation of Thr, G and its homologue. EMBO. J 12:3111-21
Hengst L., and Reed S. I. (1996) Translational contral of p27Kip accumulation during the cell cycle. Science 271:1861-4
Hirokazu A., Kiyoshi K., and Isamu H. (1989) The effects of 1,2,3,4,6-penta-ο-galloyl-β-D-glucose on rat liver mitochondrial repiration. Chem. Pharm. Bull. 37:1341-4
Hiroyuki Takahashi, Masafumi Menjo, Makoto Nakanishi., et al. (2000) Cdk4 activation is dependent on the subunit rearrangement in the complexes. Biochem.＆Bioph. Res. Comm. 267:388-93
Igagashi M., Nagata A., Jinno S., et al. (1991) Wee1(＋) like gene in human cells. Nature 353:80-3
John F. Boylan, Diane M. Sharp, Lynn Leffet, Alex Bowers, and Weijun Pan (1999) Analysis of site-specific phosphorylation of retinoblastoma protein during cell cycle progression. Exp. Cell Res. 248:110-4
Kato, J. (1999) Induction of S phase by G1 regulatory factors. Frontiers in Bioscience. 4:D787-92
Kiyoshi K., and Takashi T. (1999) Inhibitory effects of tannins of NADH dehydrogenase activity of bovine heart mitochondrial complex I. Biol. Pharm. Bull. 22:240-3
Kiyoshi K., Hirokazu A., et al. (1990) Inhibitory effects of Galloylglucose on nicotinamide adenine dinucleotide dehydrogenase of the aerobic respiratory chain of Echerichia Coli. Chem. Pharm. Bull. 38:474-6
Kiyoshi K., Hirokazu A., et al. (1993) Inhibitory effects of Tannins on NADH dehydrogenase of various organisms. Biol. Pharm. Bull. 16:716-8
Koihchi O., Tetsuyas S., Kiyoshi K., Yoshiaki H., et al. (2000) Pentagalloylglucose, an antisecretory component of Paeoniae Radix, inhibits gastric H＋,K＋-ATPase. Clinica Chimica Acta. 290:159-67
Krek W., and Nigg E. A. (1991) Differential phosphorylation of vertebrate p34cdc2 kinase at the G1/s and G2/M transitions of the cell cycle: identification of majr phosphorylation sites. EMBO. J 10:305-16
Labaer J., M. D. Garett, and E. Harlow (1997) New functional activities for p21 family CDK inhibitors. Gene＆Dev. 11:847-62
Li R., Waga S., Hannon G. J., et al. (1994) Differential effects by the p21 CDK inhibitor on PCNA-dependent DNA replication and repair. Nature 371:534-7
Lin J., C. Reichner, X. Wu, and A. J. Levine (1996) Analysis of wild-type and mutant p21WAF-1 gene activities. Mol. Biol. Cell 16:1786-93
Liu M., Lee M. H., Cohen M., Bommakanti M., and Freedman L. P. (1996) Transcriptional activation of Cdk4 inhibitor p21 by Vit D3 leads to the induced differentiation of the myelomonocyte cell line U937. Genes＆Dev. 10:142-53
Lundberg A. S., and R. A. Weinberg (1998) Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-CDK complexes. Mol. Cell. Boil. 18：753-61
M. H. Pan, S-Y. Lin-Shiau, C. T. Ho, J. H. Lin, and J. K. Lin (2000) Suppression of lipopolysaccharide-induced nuclear factor —κB activity by theaflavin 3,3’-digallate from black tea and other polyphenols through down-regulation of IκB kinase activity in macrophage. Biochem. Pharm. 59:357-67
Matsusime H., D.E. Qulle, S.A. Shurtleff, M. Shibuya, C.J. Sherr, and J-Y Kato (1994) D-type cyclin-dependent kinase activity in mammalian cells. Mol. Cell. Biol. 140：2066-76
Mengeng Cheng, Charles J. Sherr., et al. (1999) The p21Cip and p27Kip1 CDK inhibitors are essential activators of cyclin D-dependent kinase in murine fibroblasts. EMBO. J. 18:1571-83
Mineo S., Metori K., Renard J., Satoh T., and Matsumoto H. (1985) Effects of medicinal plant extract on sialidase activity. Yakugaku Zasshi 105:562-8
Nigg E. A. (1996) Cyclin-dependent kinase 7: at the cross-roads of transcription, DNA repair and cell cycle control? Current Opinion in Cell Biology. 8(3):312-7
O'Connor P. M. (1997) Mammalian G1 and G2 phase checkpoints. Cancer Surveys. 29:151-82
Ohi R. and Gould K. L. (1999) Regulating the onset of mitosis. Current Opinion in Cell Biology. 11(2):267-73
Ohtani K. (1999) Implication of transcription factor E2F in regulation of DNA replication. Frontiers in Bioscience. 4:D793-804
Orlowski C. C. and Furlanetto R. W. (1996) The mammalian cell cycle in normal and abnormal growth. Endocrinology & Metabolism Clinics of North America. 25(3):491-502
Pagono M., Tam S. W., and Rolfe M. (1995) role of the ubiquitine-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science 269:682-5
Poluha W., Poluha P. K., and Ross A. H. (1996) The cyclin-dependent kinase inhibitor p21 (WAF1) is required for survival of different neuroblastoma cells. Mol. Cell. Biol. 16:1335-41
Polyak K., Lee M. H., Erdjument-Bromega H., et al. (1994) Cloning of p27Kip1, a cyclin-dependent kinase inhibitor and potential mediator of extracellular antimitogenic signals. Cell 78:59-66
Quelle D. E., Ashmun R. A., Sherr C. J., et al. (1993) Over expression of mouse D-type cyclins accelerates G1 phase in rodent fibroblasts. Genes. Dev. 7:1559-71
Resnitszky D., Gossen M., Bujard H., and Redd S. I. (1994) Acceleration of G1/S phase transition by expression of cyclin D1 and E with an inducible system. Mol. Cell. Biol. 14:1669-79
Russell P., and Nurse P. (1987) Negative regulation of mitosis by wee1＋, a gene encoding a protein kinase homolog. Cell 49:559-67
Russo A. A., P. D. Jeffrey, A. K. Patten, J. Mssaguè, and N. P. Pavletich. (1996) Crystal structure of the p27Kip1 cyclin dependent kinase inhibitor bound to the cyclinA-Cdk2 complex. Nature 382:325-31
Sakai Y., Ose T., Nagase H., Kito H., Sato T., Kawai M., and Mizuno M. (1989) Effects of constituents of Paeony Root on the mutagenicity of benzo〔α〕pyrene. Eisei Kagaku 35:433-43
Sherr C. J. (1996) Cancer cell cycle. Science 274：1672-77
Shibutani S., Nagasawa T., Dura H., Nonaka G., and Nishioka I. (1981) Effects of extract from Paeonia Radix on urea-nitrogen concentration in rat serum. Chem. Pharm. Bull. (Tokyo) 29:874-8
Shinji Minami, Naoko Ohtani-Fujita., et al. (1997) Molecular cloning and characterization of the human p27Kip1 gene promoter. FEBS Letters. 411:1-6
Solomon M. J., Lee T., and Kirschner M. W. (1992) Role of phosphorylation in p34cdc2 activation: identification of an activating kinase. Mol. Biol. Cell 3:13-27
Soos. T. J., A. Koff., et al. (1996) Formation of p27-CDK complexes during the human mitotic cell cycle. Cell growth＆Differ. 7:135-46
Sovak M. A., Sonenshein G. E., et al. (1997) Aberrant nuclear factor-kappaB/Rel expression and pathogenesis of breast cancer. J. Clin. Invest. 100:2952-60
Strausfeld U., Labbe J. C., Fesquet D., et al ( ) Dephosphorylation and activation of p34cdc2, cyclin B complex in vitro by human CDC25 proteins. Nature 351:242-5
Sugicawa E., Ohashi M., et al. (1999) Inhibition of mutant p53 phosphorylation at ser15 or ser315 partially restore the function of wild-type p53. Biochem. Biophy. Res. Commun. 261:256-63
Takizawa C. G., and Morgan D. O. (2000) Control of mitosis by changes in the subcellular location of cyclin-B1-Cdk1 and Cdc25C. Current Opinion in Cell Biology. 12(6):658-65
Tamrakar S., Rubin E., and Ludlow J. W. (2000) Role of pRB dephosphorylation in cell cycle regulation. Frontiers in Bioscience. 5:D121-37
Timchenko N. A., and Darlington G. J. (1996) CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell poliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. Genes. Dev. 10:804-15
Tomoda K. and Kato J. (1997) Cdk inhibiting proteins. Japanese Journal of Cancer & Chemotherapy. 24(11):1407-13
Toshimitso H., Katsuyoshi N., et al. (1989) Pentagalloylglucose, a xanthine oxidase inhibitor from a paraguayan crud drug, “Molle-I”. J. Natural Plant 52:210-1
Toyoshima H., and Huter T. (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78:67-74
Tsai L. H., Harlow E., and Meyerson M. (1991) Isolation of human CDK2 gene that encodes the cyclin A- and adenovirus E1A- associated p33 kinase. Nature 353：174-77
Waga S., Hannon G. J., Beah D., et al. (1994) The p21 inhibitor of cyclin-dependent kinases control DNA replication by interaction with PCNA. Nature 369:574-8
Wu L., Yee A., Liu L., et al. (1994) Molecular cloning of the human CAK, gene encoding a cyclin-dependent kinase —activating kinase. Oncogene 9:2089-96
References
A. J. Wong, J.M. Ruppert, S. H. Bigner, C. H. Grzeschik, P. A. Humphrey, D. S. Bigner, and B. Vogelstein (1992) Structural alterations of the epidermal growth factor receptor gene in human gliomas. PNAS. 89: 2965-2969
Adamson E. D., and Wiley L. M. (1997) The EGFR gene family in embryonic cell activities. Current Topics in Developmental Biology. 35:71-120
Angel P. and Karin M. (1991) The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochimica et Biophysica Acta. 1072:129-57
A. Bonni, D. A. Frank, C. Schindler, and M. E. Greenburg. (1993) Characterization of a pathway for ciliary neurotrophic factor signaling to the nucleus. Science 262:1575
Baxter N. J., Lilley T. H. Haslam E., and Williamson M. P. (1997) Multiple interactions between polyphenols and a salivary proline-rich protein repeat result in complexation and precipitation. Biochemistry 36:5566-77
Bhat N. R., Zhang P., and Hogan E. L. (1995) Thrombin activates MAP kinase in astrocytes. J. Cell Physiol. 165:417-24
Cao X., A. Tay, G. R. Guy, and Y. H. Tan (1996) Activation and association of Stat3 with v-Src-transformed by the Src oncoprotein. Mol. Cell. Biol. 16:1595-1603
Catlett-Falcone R., Landowski T. H., Jove R., et al. (1999) Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity 10:105-15
Coffer P. J., Burgering B. M., Peppelenbosch M. P., et al. (1995) UV activation of receptor tyrosine kinase activity. Oncogene 11:561-9
Cohen S. (1962) Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the newborn animal. JBC 237:1555-62
Darnell JE. Jr. (1997) STATs and gene regulation. Science 277:1630-5
Darnell JE. Jr., Kerr J. M., and Stark G. R. (1994) JAK-STAT pathways and transcruptional activation in reponse to INFs and other extracellular signalling proteins. Science 264:1415-21
Daub H., Wallasch C., Lankenau A., Herrlich A., and Ullrich A. (1997) Signal characteristics of G protein-transactivated EGF receptor. EMBO.J. 16:101-13
Daub H., Weiss Fu, Wallasch C., and Ullrich A. (1996) A role of transactivation of the EGF receptor in signaling by G protein-coupled recptors. Nature 379:557-60
Davis R. J. (1993) The mitogen-activated protein kinase signal transduction pathway. Journal of Biological Chemistry. 268(20):14553-6
Davis R. J. (1994) MAPKs：a new JNK expands the groups. TIBS 19:470-3
Doun G., Rapp U. R. et al. (1994) The ins and outs of Raf kinase. TIBS 19:474-80
Frédéric B., Dan M., et al. (1999) The jun kinase 2 isoform is preferentially required for epidermal growth factor- induced transformation of human A549 lung carcinoma cells. Mol. Cell Biol. 19:1938-49
Garcia R. and Jove R. (1998) Activation of STAT transcription factors in oncogenic tyrosine kinase signaling. Journal of Biomedical Science. 5:79-85
Guilian N., Hua Yu., et al. (1999) Gene therapy with dominent negative Stat3 supresses growth of the murine melanoma B16 in vivo. Cancer Res. 59 :5059-63
Gille H., Sharrocks A. D., and Shaw P. E. (1992) Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358:414-7
H. B. Sadowski, K. Shuai, JE. Darnell Jr., and M. Z. Gliman. (1997) A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science 261:1739
Haeder M. M., Rutsch G., K. Molling, et al. (1988) Epidermal growth factor receptor expression in human lung cancer cell lines. Cancer Res. 48:1132-6
Henry B. S. and Michael Z. G. (1993) Cell-free activation of a DNA binding protein by epidermal growth factor. Nature 362:79-83
Hill C. S., and Treisman R. (1995) Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 80:199-211
Honneger A. M., Schmidt A., Ullrich A. and Schlessinger J. (1990) Evidence for epidermal growth factor (EGF)- induced intermolecular autophosphorylation of the EGF receptors in living cells. Mol. Cell. Biol. 10:4035-44
Hu P., Margolis B., Skolnik E. Y., Lammers R., Ullrich A., and Schlessinger J. (1992) Interaction of phophatidylinosital 3-kinase- associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mol. Cell. Biol. 12:981-90
Ihle J. N. (1996) STATs：signal transducers and activators of transcription. Cell 84:331-4
Jacqueline F. B. and Darnell JE. JR. (1999) Stat3 as an oncogene. Cell 98:295-303
Jennifer R. G., D. J. Tweardy, et al. (1998) Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor-mediated cell growth in vitro. J. Clin. Invest. 102:1385-92
John I. S. and Jennifer R. G. (2000) STAT signaling in head and neck cancer. Oncogene 19:2489-95
Johnson N. L. and Johnson G. L. (1996) Signal transduction pathways regulated by mitogen-activated/ extracellular response kinase kinase kinase induce cell death. JBC. 271:3229-37
Knebel A., Rahmsdorf H. J., Ullrich A., and Herrlich P. (1996) Dephosphorylation of receptor tyrosine kinase as target of regulation by radiation, oxidants or alkylating agent. EMBO. J. 15:5314-25
L'Allemain G. (1994) Deciphering the MAP kinase pathway. Progress in Growth Factor Research. 5:291-334
Lammers R., van Obberghen E., Balloti R., Schlessinger J., and Ullrich A. (1990) Transphosphorylation as a possible mechanism for insulin and epidermal growth factor receptor activation. JBC. 265:16886-90
Lin W. W., and Hsu Y. W. (2000) Cycloheximide-induced cPLA(2) activation is via the MKP-1 down-regulation and ERK activation. Cellular Signalling 12:457-61
Liu X., and Pawson T. (1991) The epidermal growth factor receptor phosphorylates GTPase activating protein (GAP) at tyr-460, adjacent to GAP SH2 domain. Mol. Cell. Biol. 11:2511-6
M. Haeder, M. Rotsch, G. Bepler, C. Hennig, K. Havemann, B. Heimann, and K. Moelling (1988) Epidermal growth factor receptor expression in human lung cancer cell lines. Cancer Res. 48: 1132-1136.
M. Hibi, A. Lin, T. Smeal, A. Minden, and M. Karin (1993) Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev. 7: 2135-2148
M. Lund-Johansen, R. Bjerkvig, P. A. Humphrey, S. H. Bigner, D. D. Bigner, and O. D. Laerum (1990) Effect of epidermal growth factor on glioma cell growth, migration, and invasion in vitro. Cancer Res. 50: 6039-6044
M. Reiss, E. B. Stash, V. F. Vellucci, and Z. L. Zhou (1991) Activation of the autocrine transforming growth factor alpha pathway in human squamous carcinoma cells. Cancer Res. 51: 6254-6262
Margolis B. (1992) Proteins with SH2 domains：transducers in the tyrosine kinase signaling pathway. Cell growth＆Diff. 3:73-80
Margolis B., Schlessinger J. et al. (1989) EGF induces tyrosine phosphorylation of phospholipase C—II: a potential mehanism for EGF receptor signaling. Cell 57:1101-7
Meisenhelder J., Suh P. G., Rhee S. G., and Hunter T. (1989) Phospholipase C-γ is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro. Cell 57:1109-22
Monaghan P., Ormerod M. G., and O'Hare M. J. (1990) Epidermal growth factor receptors and EGF-responsiveness of the human breast-carcinoma cell line PMC42. International Journal of Cancer. 46(5):935-43
Murray N. J., Williamson M. P., Lilley T. H., and Haslam E. (1994) Study of the interaction between salivary proline-rich proteins and a polyphenol by 1H-NMR spectroscopy. European Journal of Biochemistry. 219:923-35
Olga Potapova, Ali Haghighi, Frédéric Bost, Chaoting Liu, Michael J. Birrer, Ruth Gjerset, and Dan Mercola (1997) The Jun Kinase/Stress-activated Protein Kinase Pathway Functions to Regulate DNA Repair and Inhibition of the Pathway Sensitizes Tumor Cells to Cisplatin. J. Biol. Chem. 272: 14041-14044
Ozanne B., Richards C. S., Hendler F., Burns D., and Gusterson B., (1986) Over-expression of the EGF receptor is a hallmark of squamous cell carcinomas. Journal of Pathology. 149(1):9-14
Peter O. H., Esther Z., Norbert P., and Ullrich A. (1999) Epidermal growth factor receptors：critical mediators of multiple receptor pathways. Curr. Opi. in Cell Biol. 11:184-9
Rusch V., D. Klimtra, E. Venkotraman et al. (1997) Overexpression of epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but doesn’t predict tumor progression. Clin. Cancer Res. 3:515-22
Rusch V., Klimstra D., Venkatraman E., Pisters P. W., Langenfeld J., and Dmitrovsky E. (1997) Overexpression of the epidermal growth factor receptor and its ligand transforming growth factor alpha is frequent in resectable non-small cell lung cancer but does not predict tumor progression. Clinical Cancer Res. 3(4):515-22
Sadowski H. B., and M. Z. Gilman (1993) Cell-free activation of a DNA- binding protein by epidermal growth factor. Nature 361:79-83
Schindler C., and Darnell JE. Jr. (1995) Transcriptional responses to polypeptide ligands：the JAK-STAT pathway. Annu. Rev. Biochem. 64:621-51
Shaui K., Ziomeicki A., Wilk A. F. et al. (1993) polypeptide signaling to the nucleus through tyrosine phosphorylation of JAK and Stat proteins. Nature 366:580-3
Silvennoinen O., C. Schindler, J. Schlessinger, and D. E. Levy (1993) Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. Science 261:1736-9
Songyang Z., Contley L. C. et al. (1993) SH2 domains recognize specific phosphopeptide sequence. Cell 72:767-78
Tanaka T., Zhang H., Jiang Z. H., and Kouno I. (1997) Relationship between hydrophobicity and structure of hydrolyzable tannins, and association of tannins with crude drug constituents in aqueous solution. Chemical & Pharmaceutical Bulletin 45:1891-7
Taylor J. M., Mitchell W. M., and Cohen S. (1972) Epidermal growth factor：physical and chemical properties. JBC. 247:5928-34
Ullrich A., and Schlessinger J. (1990) Signal transduction by receptors with tyrosine kinase activity. Cell 61:203-12
Verheij M., Bose R., Lin X. H., Yao B., Jarvis W. D., Grant S., Birrer M. J., Szabo E., Zon L. I., Kyriakis J. M., Haimovitz-Friedman A., Fuks Z., and Kolesnick R. N. (1996) Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature 380:75-9
Wagner B. J., T. E. Hayes, C. J. Hoban, and B. H. Cochran (1990) The SIF binding element confers sis/PDGF inducibility onto the c—fos promoter. EMBO. J. 9:4477-84
X. Y. Fu, J. J. Zhang (1993) Transcription factor p91 interacts with the epidermal growth factor receptor and mediates the activation of the c-fos gene promoter. Cell 74:435-45
Yu C. L., R. Jove et al. (1995) Enhanced DNA-binding activity of a Stat3-relatied protein in cells tranformed by the Src oncoprotein. Science:269:81
Zhong C. R., and H. Hanafusa et al. (1996) Unique signal transduction of Eyk : constitutive stimulation of the JAK-STAT pathway by an oncogenic receptor-type tyrosine kinase. EMBO. J. 15:4515-25
Zhong Z., Wen Z., Darnell JE. Jr. (1994) Stat3：a STAT family member activated by tyrosine phosphorylation in the reponse to epidermal growth factor and interleukin-6. Scince 264:95-8