簡易檢索 / 詳目顯示

研究生: 羅雅勤
Lo, Ya-Chin
論文名稱: 研究抗癌藥物活化STAT3的機轉
The study of the mechanisms by which anticancer agents activate STAT3 oncoprotein
指導教授: 蘇五洲
Su, Wu-Chou
劉校生
Liu, H.S.
學位類別: 碩士
Master
系所名稱: 醫學院 - 分子醫學研究所
Institute of Molecular Medicine
論文出版年: 2005
畢業學年度: 93
語文別: 英文
論文頁數: 60
中文關鍵詞: 抗癌藥物氧化壓力
外文關鍵詞: TAXOL, Oxidative stress, STAT3
相關次數: 點閱:73下載:1
分享至:
查詢本校圖書館目錄 查詢臺灣博碩士論文知識加值系統 勘誤回報
  •   STAT3為一細胞內轉錄因子,許多報導指出,STAT3能夠誘導一系列關於細胞週期轉換、細胞增生及細胞存活相關基因的表現,例如cyclin D1、p21/Waf1、c-Myc 以及Bcl-xl。因此,我們認為STAT3活化的訊息傳導路徑不僅能提供細胞生長的優勢,或許它也對細胞抗藥性質有所貢獻。在先前的實驗結果證明人類肺腺癌細胞-PC14PE6/AS2-主要是透過IL6/gp130/Jak2訊息傳導路徑使STAT3 持續活化。我們也嘗試探討STAT3的活化與細胞對抗腫瘤藥物之抗藥性的關聯。實驗結果顯示在藥物處理的早期(約3小時),大部份測試的藥物均會提高PC14PE6/AS2細胞中活化性STAT3的量,隨後表現出不同程度下降。同時也證明了使用JAK2抑制藥物-AG490-處理細胞可以成功抑制STAT3活化的表現,顯示STAT3的訊息傳導透過JAK2調控。因此,為何抗腫瘤藥物在早期可活化STAT3以及背後隱藏的機轉,是我們主要研究的一重點 。我們認為抗癌藥物是透過產生氧化壓力(reactive oxygen species)導致去磷酸酶失去抑制磷酸酶的功能。在PC14PE6/AS2細胞中,我們以偵測氧化壓力的探針-DCFH-DA-發現抗癌藥物確實引發了氧化壓力。而抗癌藥物所引發的氧化壓力可以成功的被DPI(抑制含有黃素蛋白的氧化酵素)、Rotenone(抑制粒線體呼吸鏈第一群)、Antimycin A(抑制粒線體呼吸鏈第三群)三種氧化壓力抑制藥物所抑制,這3種藥物也有效的抑制住抗癌藥物所引起的STAT3活化。但是其他的氧化壓力抑制劑例如:Catalase, NAC卻無法有效的抑制抗癌藥物所引起的STAT3活化,因此我們推斷抗癌藥物所引發的氧化壓力主要來自於粒線體。另一方面,我們選擇了文獻曾經報導會被氧化壓力抑制功能的去磷酸酶-PTP1B-是否也被抗癌藥物引發的氧化壓力所抑制,但很可惜的,我們並沒有觀察到此現象。但隨後我們發現了另一可能的機轉,氧化壓力曾被報導在血管肌肉細胞中發現透過活化PKC-而活化了下游磷酸酶,我們利用rottlerin抑制PKC-發現抗癌藥物所引起的STAT3活化也會部分被抑制,也許PKC-/PYK2/JAK2的機轉參與其中。綜合以上實驗結果,我們推論以活化性STAT3為標的是改進癌症治療之可行方針。

      Stat3, one of the 7 known STAT (Signal Transducers and Activators of Transcription) family members, is frequently constitutively activated in malignant cells1. Activation of Stat3 is involved in regulating many genes such as cell cycle progression, cellular proliferation and survival. In our system, constitutively activated Stat3 in human lung adenocarcinoma cell line --PC14PE6/AS2, mediated by IL6/gp130/Jak2 pathway, was demonstrated. Upon treatment with anti-cancer agents, the activation of Stat3 in PC14PE6/AS2 cells was enhanced at earlier period (around 3 hours), and then declined gradually. The further activation of Stat3 in PC14PE6/AS2 cells by paclitaxel could be abolished by adding Jak2 inhibitor – AG490 – indicates that Jak2 mediates the reaction. For the mechanisms underlying the activation of Jak2 by anticancer agents, we suspect the induction of ROS and subsequent deactivation of tyrosine phosphatase may play a role. Using the redox-sensitive fluorescence probe DCFH-DA, we found that anti-cancer agent, paclitaxel, stimulates ROS production in PC14PE6/AS2 cells. Generation of ROS was suppressed by diphenylene iodonium (DPI), an inhibitor of flavoprotein-dependent oxidases, Rotenone, an inhibitor of mitochondrial respiratory chain complex I, and Antimycin A, an inhibitor of mitochondrial respiratory chain complex III. The activation of Stat3 in PC14PE6/AS2 cells by paclitaxel is also inhibited by the pretreatment of the above three compounds. Other inhibitors of NAC or catalase did not abolish Stat3 activation by paclitaxel. Taken together, paclitaxel induces ROS generation is likely through a mitochondrial-mediated pathway. In the other part, we suspect that generation of ROS by paclitaxel may transiently inactivate PTP-1B and then switch the equilibrium towards autophosphorylation of Jak kinases. Although this phenomenon was not observed, we found another pathway may partially involved STAT3 activation induced by paclitaxel. H2O2-induced activation of PKC- is reported to be independent from tyrosine phosphatase inhibition. Inhibition of PKCusing rottlerin supported that PKC kinase activity is required for both baseline and paclitaxel-induced STAT3 tyrosine phosphorylation. The paclitaxel-induced STAT3 activation resulted in upregulation of Bcl-2 protein, which may contribute to the relative resistance to paclitaxel’s cytotoxicity in PC14PE6/AS2 than in A549 cells. With a better understanding of how anticancer agents regulate Stat3 activation, we may have chances to find new targets for overcoming tumor drug resistance.

    Abstract in Chinese…………………………………………… I Abstract in English…………………………………………… III Acknowledgement………………………………………………… V Index……………………………………………………………… VII List of Figures………………………………………………… IX 1. Introduction 1.1 STATs………………………………………………………… 1 1.1.1 STAT family members and chromosomal localization ………………………………………………………… 1 1.1.2 The JAK-STAT signaling……………………………… 2 1.1.3 The biological function of STAT3………………… 3 1.2 Anticancer agents can activate Stat3………………… 5 1.2.1 Taxol induce ROS generation……………………… 5 1.3 Reactive oxygen species……………………………………… 6 1.3.1 Source of reactive oxygen species (ROS)……………. 8 1.3.2 Reactive oxygen species (ROS) as second messengers in signal transduction………………………………………8 1.4 Inhibitors of JAK-STAT signal transduction…………………10 1.4.1 Tyrosine phosphatases inactivated by oxidants…….. 11 2. Materials and Methods 2.1 Reagents……………………………………………………… 12 2.2 Cell lines and culture…………………………………… 12 2.3 Cytotoxic assay – MTT method…………………………… 14 2.4 Western blot analysis……………………………………… 15 2.5 Measurement of intracellular ROS generation………… 16 2.6 PTP1B activity assay……………………………………… 17 2.7 Isolation of total RNA—TRIzol method…………………20 2.8 Reverse transcriptase-polymerase chain reaction (RT-PCR) ……………………………………………………… 21 2.9 Data and statistics …………………………………………… 22 3. Results 3.1 Palitaxel activates or deactivates STAT3 in different cell lines …………………………………………………………… 23 3.2 Paclitaxel dose not change STAT3 serine-727 phosphorylation in PC14PE6/AS2 and A549 cells …………………………… 24 3.3 Paclitaxel stimulates JAK2 tyrosine phosphorylation in PC14PE6/AS2 cells…………………………………………… 25 3.4 Paclitaxel induced oxidative stress in PC14PE6/AS2 cells… 26 3.5 Effects of antioxidants on paclitaxel-induced ROS production    ……………………………………………………… 26 3.6 Paclitaxel didn’t inhibit PTP1B activity……………………… 28 3.7 PKC- may involved in the paclitaxel induced STAT3 activation ………………………………………………………… 29 3.8 Expression of Bcl-2 in PC14PE6/AS2 cells after treating with paclitaxel………………………………………………………… 29 3.9 The SOCS-3 expression in PC14PE6/AS2 and A549 cells……………………………………………………………… 29 3.10 The SHP-2 expression in PC14PE6/AS2 and A549 cells……………………………………………………………… 30 4. Discussion…………………………………………………… 31 5. References……………………………………………………35

    Akira, S., 2000. Roles of STAT3 defined by tissue-specific gene targeting. Oncogene. 19, 2607-2611.
    Babior, B. M., Lambeth, J. D. and Nauseef, W., 2002. The neutrophil NADPH oxidase. Arch Biochem Biophys. 397, 342-344.
    Boulton, T. G., Zhong, Z., Wen, Z., Darnell, J. E., Jr., Stahl, N. and Yancopoulos, G. D., 1995. STAT3 activation by cytokines utilizing gp130 and related transducers involves a secondary modification requiring an H7-sensitive kinase. Proc Natl Acad Sci U S A. 92, 6915-6919.
    Bowman, T., Garcia, R., Turkson, J. and Jove, R., 2000. STATs in oncogenesis. Oncogene. 19, 2474-2488.
    Brivanlou, A. H. and Darnell, J. E., Jr., 2002. Signal transduction and the control of gene expression. Science. 295, 813-818.
    Bromberg, J. and Darnell, J. E., Jr., 2000. The role of STATs in transcriptional control and their impact on cellular function. Oncogene. 19, 2468-2473.
    Chandra, J., Samali, A. and Orrenius, S., 2000. Triggering and modulation of apoptosis by oxidative stress. Free Radic Biol Med. 29, 323-333.
    Chen, X., Vinkemeier, U., Zhao, Y., Jeruzalmi, D., Darnell, J. E., Jr. and Kuriyan, J., 1998. Crystal structure of a tyrosine phosphorylated STAT-1 dimer bound to DNA. Cell. 93, 827-839.
    Chin, Y. E., Kitagawa, M., Kuida, K., Flavell, R. A. and Fu, X. Y., 1997. Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. Mol Cell Biol. 17, 5328-5337.
    Chin, Y. E., Kitagawa, M., Su, W. C., You, Z. H., Iwamoto, Y. and Fu, X. Y., 1996. Cell growth arrest and induction of cyclin-dependent kinase inhibitor p21 WAF1/CIP1 mediated by STAT1. Science. 272, 719-722.
    Chung, C. D., Liao, J., Liu, B., Rao, X., Jay, P., Berta, P. and Shuai, K., 1997. Specific inhibition of Stat3 signal transduction by PIAS3. Science. 278, 1803-1805.
    Copeland, N. G., Gilbert, D. J., Schindler, C., Zhong, Z., Wen, Z., Darnell, J. E., Jr., Mui, A. L., Miyajima, A., Quelle, F. W., Ihle, J. N. and et al., 1995. Distribution of the mammalian Stat gene family in mouse chromosomes. Genomics. 29, 225-228.
    Darnell, J. E., Jr., 1997. STATs and gene regulation. Science. 277, 1630-1635.
    David, M., Petricoin, E., 3rd, Benjamin, C., Pine, R., Weber, M. J. and Larner, A. C., 1995. Requirement for MAP kinase (ERK2) activity in interferon alpha- and interferon beta-stimulated gene expression through STAT proteins. Science. 269, 1721-1723.
    Decker, T. and Kovarik, P., 2000. Serine phosphorylation of STATs. Oncogene. 19, 2628-2637.
    Dent, P., Jarvis, W. D., Birrer, M. J., Fisher, P. B., Schmidt-Ullrich, R. K. and Grant, S., 1998. The roles of signaling by the p42/p44 mitogen-activated protein (MAP) kinase pathway; a potential route to radio- and chemo-sensitization of tumor cells resulting in the induction of apoptosis and loss of clonogenicity. Leukemia. 12, 1843-1850.
    Endo, T. A., Masuhara, M., Yokouchi, M., Suzuki, R., Sakamoto, H., Mitsui, K., Matsumoto, A., Tanimura, S., Ohtsubo, M., Misawa, H., Miyazaki, T., Leonor, N., Taniguchi, T., Fujita, T., Kanakura, Y., Komiya, S. and Yoshimura, A., 1997. A new protein containing an SH2 domain that inhibits JAK kinases. Nature. 387, 921-924.
    Finkel, T. and Holbrook, N. J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature. 408, 239-247.
    Frank, G. D., Mifune, M., Inagami, T., Ohba, M., Sasaki, T., Higashiyama, S., Dempsey, P. J. and Eguchi, S., 2003. Distinct mechanisms of receptor and nonreceptor tyrosine kinase activation by reactive oxygen species in vascular smooth muscle cells: role of metalloprotease and protein kinase C-delta. Mol Cell Biol. 23, 1581-1589.
    Frantsve, J., Schwaller, J., Sternberg, D. W., Kutok, J. and Gilliland, D. G., 2001. Socs-1 inhibits TEL-JAK2-mediated transformation of hematopoietic cells through inhibition of JAK2 kinase activity and induction of proteasome-mediated degradation. Mol Cell Biol. 21, 3547-3557.
    Geiszt, M., Kopp, J. B., Varnai, P. and Leto, T. L., 2000. Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A. 97, 8010-8014.
    Griendling, K. K., Sorescu, D. and Ushio-Fukai, M., 2000. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 86, 494-501.
    Horwitz, S. B., 1992. Mechanism of action of taxol. Trends Pharmacol Sci. 13, 134-136.
    Ihle, J. N., 1996. STATs: signal transducers and activators of transcription. Cell. 84,331-334.
    Jain, N., Zhang, T., Kee, W. H., Li, W. and Cao, X., 1999. Protein kinase C delta associates with and phosphorylates Stat3 in an interleukin-6-dependent manner. J Biol Chem. 274, 24392-24400.
    Janssen, Y. M., Van Houten, B., Borm, P. J. and Mossman, B. T., 1993. Cell and tissue responses to oxidative damage. Lab Invest. 69, 261-274.
    Jordan, M. A., Wendell, K., Gardiner, S., Derry, W. B., Copp, H. and Wilson, L., 1996. Mitotic block induced in HeLa cells by low concentrations of paclitaxel (Taxol) results in abnormal mitotic exit and apoptotic cell death. Cancer Res. 56, 816-825.
    Kamura, T., Sato, S., Haque, D., Liu, L., Kaelin, W. G., Jr., Conaway, R. C. and Conaway, J. W., 1998. The Elongin BC complex interacts with the conserved SOCS-box motif present in members of the SOCS, ras, WD-40 repeat, and ankyrin repeat families. Genes Dev. 12, 3872-3881.
    Kisseleva, T., Bhattacharya, S., Braunstein, J. and Schindler, C. W., 2002. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 285, 1-24.
    Klingmuller, U., Lorenz, U., Cantley, L. C., Neel, B. G. and Lodish, H. F., 1995. Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals. Cell. 80, 729-738.
    Krebs, D. L. and Hilton, D. J., 2001. SOCS proteins: negative regulators of cytokine signaling. Stem Cells. 19, 378-387.
    Kumar, N., 1981. Taxol-induced polymerization of purified tubulin. Mechanism of action. J Biol Chem. 256, 10435-10441.
    Lee, S. R., Kwon, K. S., Kim, S. R. and Rhee, S. G., 1998. Reversible inactivation of protein-tyrosine phosphatase 1B in A431 cells stimulated with epidermal growth factor. J Biol Chem. 273, 15366-15372.
    Levitzki, A., 1992. Tyrphostins: tyrosine kinase blockers as novel antiproliferative agents and dissectors of signal transduction. Faseb J. 6, 3275-3282.
    Levy, D. E. and Darnell, J. E., Jr., 2002. Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 3, 651-662.
    Li, J. M. and Shah, A. M., 2002. Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells. J Biol Chem. 277, 19952-19960.
    Liu, B., Du, L. and Hong, J. S., 2000. Naloxone protects rat dopaminergic neurons against inflammatory damage through inhibition of microglia activation and superoxide generation. J Pharmacol Exp Ther. 293, 607-617.
    Liu, B., Liao, J., Rao, X., Kushner, S. A., Chung, C. D., Chang, D. D. and Shuai, K., 1998. Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci U S A. 95, 10626-10631.
    Meydan, N., Grunberger, T., Dadi, H., Shahar, M., Arpaia, E., Lapidot, Z., Leeder, J. S., Freedman, M., Cohen, A., Gazit, A., Levitzki, A. and Roifman, C. M., 1996. Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature. 379, 645-648.
    Newton, A. C., 1997. Regulation of protein kinase C. Curr Opin Cell Biol. 9, 161-167.
    Ni, Z., Lou, W., Leman, E. S. and Gao, A. C., 2000. Inhibition of constitutively activated Stat3 signaling pathway suppresses growth of prostate cancer cells. Cancer Res. 60, 1225-1228.
    Nishizuka, Y., 1995. Protein kinase C and lipid signaling for sustained cellular responses. Faseb J. 9, 484-496.
    Pahl, H. L. and Baeuerle, P. A., 1994. Oxygen and the control of gene expression. Bioessays. 16, 497-502.
    Ram, P. A. and Waxman, D. J., 1997. Interaction of growth hormone-activated STATs with SH2-containing phosphotyrosine phosphatase SHP-1 and nuclear JAK2 tyrosine kinase. J Biol Chem. 272, 17694-17702.
    Ram, P. A. and Waxman, D. J., 1999. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J Biol Chem. 274, 35553-35561.
    Sadowski, H. B., Shuai, K., Darnell, J. E., Jr. and Gilman, M. Z., 1993. A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. Science. 261, 1739-1744.
    Saito, S., Frank, G. D., Mifune, M., Ohba, M., Utsunomiya, H., Motley, E. D., Inagami, T. and Eguchi, S., 2002. Ligand-independent trans-activation of the platelet-derived growth factor receptor by reactive oxygen species requires protein kinase C-delta and c-Src. J Biol Chem. 277, 44695-44700.
    Salmeen, A., Andersen, J. N., Myers, M. P., Meng, T. C., Hinks, J. A., Tonks, N. K. and Barford, D., 2003. Redox regulation of protein tyrosine phosphatase 1B involves a sulphenyl-amide intermediate. Nature. 423, 769-773.
    Sano, S., Itami, S., Takeda, K., Tarutani, M., Yamaguchi, Y., Miura, H., Yoshikawa, K., Akira, S. and Takeda, J., 1999. Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis. Embo J. 18, 4657-4668.
    Sarosy, G. and Reed, E., 1993. Taxol dose intensification and its clinical implications. J Natl Med Assoc. 85, 427-431.
    Schiff, P. B. and Horwitz, S. B., 1981. Taxol assembles tubulin in the absence of exogenous guanosine 5'-triphosphate or microtubule-associated proteins. Biochemistry. 20, 3247-3252.
    Schindler, C. and Darnell, J. E., Jr., 1995. Transcriptional responses to polypeptide ligands: the JAK-STAT pathway. Annu Rev Biochem. 64, 621-651.
    Schreck, R., Rieber, P. and Baeuerle, P. A., 1991. Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1. Embo J. 10, 2247-2258.
    Schuringa, J. J., Dekker, L. V., Vellenga, E. and Kruijer, W., 2001. Sequential activation of Rac-1, SEK-1/MKK-4, and protein kinase Cdelta is required for interleukin-6-induced STAT3 Ser-727 phosphorylation and transactivation. J Biol Chem. 276, 27709-27715.
    Shiose, A., Kuroda, J., Tsuruya, K., Hirai, M., Hirakata, H., Naito, S., Hattori, M., Sakaki, Y. and Sumimoto, H., 2001. A novel superoxide-producing NAD(P)H oxidase in kidney. J Biol Chem. 276, 1417-1423.
    Shuai, K., Stark, G. R., Kerr, I. M. and Darnell, J. E., Jr., 1993. A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. Science. 261, 1744-1746.
    Shultz, L. D., Schweitzer, P. A., Rajan, T. V., Yi, T., Ihle, J. N., Matthews, R. J., Thomas, M. L. and Beier, D. R., 1993. Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell. 73, 1445-1454.
    Silvennoinen, O., Schindler, C., Schlessinger, J. and Levy, D. E., 1993. Ras-independent growth factor signaling by transcription factor tyrosine phosphorylation. Science. 261, 1736-1739.
    Simon, E., Paul, J. L., Soni, T., Simon, A. and Moatti, N., 1997. Plasma and erythrocyte vitamin E content in asymptomatic hypercholesterolemic subjects. Clin Chem. 43, 285-289.
    Sun, X., Wu, F., Datta, R., Kharbanda, S. and Kufe, D., 2000. Interaction between protein kinase C delta and the c-Abl tyrosine kinase in the cellular response to oxidative stress. J Biol Chem. 275, 7470-7473.
    Sundaresan, M., Yu, Z. X., Ferrans, V. J., Irani, K. and Finkel, T., 1995. Requirement for generation of H2O2 for platelet-derived growth factor signal transduction. Science. 270, 296-299.
    Symes, A., Stahl, N., Reeves, S. A., Farruggella, T., Servidei, T., Gearan, T., Yancopoulos, G. and Fink, J. S., 1997. The protein tyrosine phosphatase SHP-2 negatively regulates ciliary neurotrophic factor induction of gene expression. Curr Biol. 7, 697-700.
    Szatrowski, T. P. and Nathan, C. F., 1991. Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res. 51, 794-798.
    Thannickal, V. J. and Fanburg, B. L., 2000. Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol. 279, L1005-1028.
    Turkson, J., Bowman, T., Adnane, J., Zhang, Y., Djeu, J. Y., Sekharam, M., Frank, D. A., Holzman, L. B., Wu, J., Sebti, S. and Jove, R., 1999. Requirement for Ras/Rac1-mediated p38 and c-Jun N-terminal kinase signaling in Stat3 transcriptional activity induced by the Src oncoprotein. Mol Cell Biol. 19, 7519-7528.
    Varbiro, G., Veres, B., Gallyas, F., Jr. and Sumegi, B., 2001. Direct effect of Taxol on free radical formation and mitochondrial permeability transition. Free Radic Biol Med. 31, 548-558.
    Wang, Y. F., Chen, C. Y., Chung, S. F., Chiou, Y. H. and Lo, H. R., 2004. Involvement of oxidative stress and caspase activation in paclitaxel-induced apoptosis of primary effusion lymphoma cells. Cancer Chemother Pharmacol. 54, 322-330.
    Woetmann, A., Nielsen, M., Christensen, S. T., Brockdorff, J., Kaltoft, K., Engel, A. M., Skov, S., Brender, C., Geisler, C., Svejgaard, A., Rygaard, J., Leick, V. and Odum, N., 1999. Inhibition of protein phosphatase 2A induces serine/threonine phosphorylation, subcellular redistribution, and functional inhibition of STAT3. Proc Natl Acad Sci U S A. 96, 10620-10625.
    Yamamoto, T., Matsuzaki, H., Konishi, H., Ono, Y. and Kikkawa, U., 2000. H(2)O(2)-induced tyrosine phosphorylation of protein kinase cdelta by a mechanism independent of inhibition of protein-tyrosine phosphatase in CHO and COS-7 cells. Biochem Biophys Res Commun. 273, 960-966.
    Yokogami, K., Wakisaka, S., Avruch, J. and Reeves, S. A., 2000. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr Biol. 10, 47-50.
    Zhong, Z., Wen, Z. and Darnell, J. E., Jr., 1994. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 264, 95-98.

    下載圖示 校內:2006-08-09公開
    校外:2006-08-09公開
    QR CODE