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*
Department of Biochemistry, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan;
Research Institute, Osaka Maternal and Child Health Center, Izumi, Osaka, Japan;
Department of Environmental Medicine, Osaka University Medical School, Osaka, Japan; and
§
Osaka University, Suita, Osaka, Japan
Stat3, a member of STAT, is activated by a variety of cytokines such as IL-6 family of cytokines, granulocyte CSF, epidermal growth factor, and leptin. A recent study with mice genetically deficient in the Stat3 gene has revealed its important role in the early embryogenesis. To assess the function of Stat3 in adult tissues, we disrupted the Stat3 gene specifically in T cells by conditional gene targeting using Cre-loxP system. In Stat3-deficient T cells, IL-6-induced proliferation was severely impaired. IL-6 did not enhance cell cycle progression, but prevented apoptosis of normal T cells. In contrast, IL-6 did not prevent apoptosis of Stat3-deficient T cells. Antiapoptotic protein, Bcl-2, was normally up-regulated in response to IL-6 even in Stat3-deficient T cells. These results demonstrate that Stat3 activation is involved in IL-6-dependent T cell proliferation through prevention of apoptosis independently of Bcl-2.
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 M. Gartsbein, A. Alt, K. Hashimoto, K. Nakajima, T. Kuroki, and T. Tennenbaum The role of protein kinase C {delta} activation and STAT3 Ser727 phosphorylation in insulin-induced keratinocyte proliferation J. Cell Sci., February 1, 2006; 119(3): 470 - 481. [Abstract] [Full Text] [PDF]
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J. L. Fornek, L. T. Tygrett, T. J. Waldschmidt, V. Poli, R. C. Rickert, and G. S. Kansas Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells Blood, February 1, 2006; 107(3): 1085 - 1091. [Abstract] [Full Text] [PDF]
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A. V. Villarino, J. S. Stumhofer, C. J. M. Saris, R. A. Kastelein, F. J. de Sauvage, and C. A. Hunter IL-27 Limits IL-2 Production during Th1 Differentiation J. Immunol., January 1, 2006; 176(1): 237 - 247. [Abstract] [Full Text] [PDF]
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 H. Mechoulam and E. A. Pierce Expression and Activation of STAT3 in Ischemia-Induced Retinopathy Invest. Ophthalmol. Vis. Sci., December 1, 2005; 46(12): 4409 - 4416. [Abstract] [Full Text] [PDF]
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M. Ikegami, J. A. Whitsett, P. C. Martis, and T. E. Weaver Reversibility of lung inflammation caused by SP-B deficiency Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L962 - L970. [Abstract] [Full Text] [PDF]
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 V. Selvaraj, D. Bunick, C. Finnigan-Bunick, R. W. Johnson, H. Wang, L. Liu, and P. S. Cooke Gene Expression Profiling of 17{beta}-Estradiol and Genistein Effects on Mouse Thymus Toxicol. Sci., September 1, 2005; 87(1): 97 - 112. [Abstract] [Full Text] [PDF]
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Y. Kato, A. Iwama, Y. Tadokoro, K. Shimoda, M. Minoguchi, S. Akira, M. Tanaka, A. Miyajima, T. Kitamura, and H. Nakauchi Selective activation of STAT5 unveils its role in stem cell self-renewal in normal and leukemic hematopoiesis J. Exp. Med., July 5, 2005; 202(1): 169 - 179. [Abstract] [Full Text] [PDF]
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R. M. McLoughlin, B. J. Jenkins, D. Grail, A. S. Williams, C. A. Fielding, C. R. Parker, M. Ernst, N. Topley, and S. A. Jones IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation PNAS, July 5, 2005; 102(27): 9589 - 9594. [Abstract] [Full Text] [PDF]
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B. J. Jenkins, A. W. Roberts, M. Najdovska, D. Grail, and M. Ernst The threshold of gp130-dependent STAT3 signaling is critical for normal regulation of hematopoiesis Blood, May 1, 2005; 105(9): 3512 - 3520. [Abstract] [Full Text] [PDF]
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G. Matarese, S. Moschos, and C. S. Mantzoros Leptin in Immunology J. Immunol., March 15, 2005; 174(6): 3137 - 3142. [Abstract] [Full Text] [PDF]
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B. A. Butcher, L. Kim, A. D. Panopoulos, S. S. Watowich, P. J. Murray, and E. Y. Denkers Cutting Edge: IL-10-Independent STAT3 Activation by Toxoplasma gondii Mediates Suppression of IL-12 and TNF-{alpha} in Host Macrophages J. Immunol., March 15, 2005; 174(6): 3148 - 3152. [Abstract] [Full Text] [PDF]
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Y. Yang, J. Ochando, A. Yopp, J. S. Bromberg, and Y. Ding IL-6 Plays a Unique Role in Initiating c-Maf Expression during Early Stage of CD4 T Cell Activation J. Immunol., March 1, 2005; 174(5): 2720 - 2729. [Abstract] [Full Text] [PDF]
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B. Ahr, M. Denizot, V. Robert-Hebmann, A. Brelot, and M. Biard-Piechaczyk Identification of the Cytoplasmic Domains of CXCR4 Involved in Jak2 and STAT3 Phosphorylation J. Biol. Chem., February 25, 2005; 280(8): 6692 - 6700. [Abstract] [Full Text] [PDF]
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N. Schick, E. J. Oakeley, N. E. Hynes, and A. Badache TEL/ETV6 Is a Signal Transducer and Activator of Transcription 3 (Stat3)-induced Repressor of Stat3 Activity J. Biol. Chem., September 10, 2004; 279(37): 38787 - 38796. [Abstract] [Full Text] [PDF]
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 R. M. Smith, N. Suleman, L. Lacerda, L. H. Opie, S. Akira, K. R. Chien, and M. N. Sack Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning Cardiovasc Res, September 1, 2004; 63(4): 611 - 616. [Abstract] [Full Text] [PDF]
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R. Sun, Z. Tian, S. Kulkarni, and B. Gao IL-6 Prevents T Cell-Mediated Hepatitis via Inhibition of NKT Cells in CD4+ T Cell- and STAT3-Dependent Manners J. Immunol., May 1, 2004; 172(9): 5648 - 5655. [Abstract] [Full Text] [PDF]
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 K. Schroder, P. J. Hertzog, T. Ravasi, and D. A. Hume Interferon-{gamma}: an overview of signals, mechanisms and functions J. Leukoc. Biol., February 1, 2004; 75(2): 163 - 189. [Abstract] [Full Text] [PDF]
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 Y. Cui, L. Huang, F. Elefteriou, G. Yang, J. M. Shelton, J. E. Giles, O. K. Oz, T. Pourbahrami, C. Y. H. Lu, J. A. Richardson, et al. Essential Role of STAT3 in Body Weight and Glucose Homeostasis Mol. Cell. Biol., January 1, 2004; 24(1): 258 - 269. [Abstract] [Full Text] [PDF]
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Y. Shen, K. Schlessinger, X. Zhu, E. Meffre, F. Quimby, D. E. Levy, and J. E. Darnell Jr. Essential Role of STAT3 in Postnatal Survival and Growth Revealed by Mice Lacking STAT3 Serine 727 Phosphorylation Mol. Cell. Biol., January 1, 2004; 24(1): 407 - 419. [Abstract] [Full Text] [PDF]
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A. Kano, M. J. Wolfgang, Q. Gao, J. Jacoby, G.-X. Chai, W. Hansen, Y. Iwamoto, J. S. Pober, R. A. Flavell, and X.-Y. Fu Endothelial Cells Require STAT3 for Protection against Endotoxin-induced Inf lammation J. Exp. Med., November 17, 2003; 198(10): 1517 - 1525. [Abstract] [Full Text] [PDF]
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Z. Percario, E. Olivetta, G. Fiorucci, G. Mangino, S. Peretti, G. Romeo, E. Affabris, and M. Federico Human immunodeficiency virus type 1 (HIV-1) Nef activates STAT3 in primary human monocyte/macrophages through the release of soluble factors: involvement of Nef domains interacting with the cell endocytotic machinery J. Leukoc. Biol., November 1, 2003; 74(5): 821 - 832. [Abstract] [Full Text] [PDF]
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S. Tomita, H.-B. Jiang, T. Ueno, S. Takagi, K. Tohi, S.-i. Maekawa, A. Miyatake, A. Furukawa, F. J. Gonzalez, J. Takeda, et al. T Cell-Specific Disruption of Arylhydrocarbon Receptor Nuclear Translocator (Arnt) Gene Causes Resistance to 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Thymic Involution J. Immunol., October 15, 2003; 171(8): 4113 - 4120. [Abstract] [Full Text] [PDF]
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A. B. Waxman, K. Mahboubi, R. G. Knickelbein, L. L. Mantell, N. Manzo, J. S. Pober, and J. A. Elias Interleukin-11 and Interleukin-6 Protect Cultured Human Endothelial Cells from H2O2-Induced Cell Death Am. J. Respir. Cell Mol. Biol., October 1, 2003; 29(4): 513 - 522. [Abstract] [Full Text] [PDF]
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A. C. Bharti, N. Donato, and B. B. Aggarwal Curcumin (Diferuloylmethane) Inhibits Constitutive and IL-6-Inducible STAT3 Phosphorylation in Human Multiple Myeloma Cells J. Immunol., October 1, 2003; 171(7): 3863 - 3871. [Abstract] [Full Text] [PDF]
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 J. M. Shillingford, K. Miyoshi, G. W. Robinson, B. Bierie, Y. Cao, M. Karin, and L. Hennighausen Proteotyping of Mammary Tissue from Transgenic and Gene Knockout Mice with Immunohistochemical Markers: a Tool To Define Developmental Lesions J. Histochem. Cytochem., May 1, 2003; 51(5): 555 - 565. [Abstract] [Full Text] [PDF]
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M. Benekli, M. R. Baer, H. Baumann, and M. Wetzler Signal transducer and activator of transcription proteins in leukemias Blood, April 15, 2003; 101(8): 2940 - 2954. [Abstract] [Full Text] [PDF]
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T. Welte, S. S. M. Zhang, T. Wang, Z. Zhang, D. G. T. Hesslein, Z. Yin, A. Kano, Y. Iwamoto, E. Li, J. E. Craft, et al. STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: A critical role of STAT3 in innate immunity PNAS, February 18, 2003; 100(4): 1879 - 1884. [Abstract] [Full Text] [PDF]
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H. Sanjo, K. Takeda, T. Tsujimura, J. Ninomiya-Tsuji, K. Matsumoto, and S. Akira TAB2 Is Essential for Prevention of Apoptosis in Fetal Liver but Not for Interleukin-1 Signaling Mol. Cell. Biol., February 15, 2003; 23(4): 1231 - 1238. [Abstract] [Full Text] [PDF]
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M. Yamada, N. Ishii, H. Asao, K. Murata, C. Kanazawa, H. Sasaki, and K. Sugamura Signal-Transducing Adaptor Molecules STAM1 and STAM2 Are Required for T-Cell Development and Survival Mol. Cell. Biol., December 15, 2002; 22(24): 8648 - 8658. [Abstract] [Full Text] [PDF]
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 M. J. Scott, C. J. Godshall, and W. G. Cheadle Jaks, STATs, Cytokines, and Sepsis Clin. Vaccine Immunol., November 1, 2002; 9(6): 1153 - 1159. [Full Text] [PDF]
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T. Atsumi, K. Ishihara, D. Kamimura, H. Ikushima, T. Ohtani, S. Hirota, H. Kobayashi, S.-J. Park, Y. Saeki, Y. Kitamura, et al. A Point Mutation of Tyr-759 in Interleukin 6 Family Cytokine Receptor Subunit gp130 Causes Autoimmune Arthritis J. Exp. Med., October 7, 2002; 196(7): 979 - 990. [Abstract] [Full Text] [PDF]
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R. C. Humphreys, B. Bierie, L. Zhao, R. Raz, D. Levy, and L. Hennighausen Deletion of Stat3 Blocks Mammary Gland Involution and Extends Functional Competence of the Secretory Epithelium in the Absence of Lactogenic Stimuli Endocrinology, September 1, 2002; 143(9): 3641 - 3650. [Abstract] [Full Text] [PDF]
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W. Li, X. Liang, C. Kellendonk, V. Poli, and R. Taub STAT3 Contributes to the Mitogenic Response of Hepatocytes during Liver Regeneration J. Biol. Chem., August 2, 2002; 277(32): 28411 - 28417. [Abstract] [Full Text] [PDF]
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R. Shen and M. H. Kaplan The Homeostasis But Not the Differentiation of T Cells Is Regulated by p27Kip1 J. Immunol., July 15, 2002; 169(2): 714 - 721. [Abstract] [Full Text] [PDF]
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 S. Sun and B. M. Steinberg PTEN is a negative regulator of STAT3 activation in human papillomavirus-infected cells J. Gen. Virol., June 1, 2002; 83(7): 1651 - 1658. [Abstract] [Full Text] [PDF]
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K. Kirito, M. Osawa, H. Morita, R. Shimizu, M. Yamamoto, A. Oda, H. Fujita, M. Tanaka, K. Nakajima, Y. Miura, et al. A functional role of Stat3 in in vivo megakaryopoiesis Blood, May 1, 2002; 99(9): 3220 - 3227. [Abstract] [Full Text] [PDF]
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 I. Vancurova, R. Wu, V. Miskolci, and S. Sun Increased p50/p50 NF-{kappa}B Activation in Human Papillomavirus Type 6- or Type 11-Induced Laryngeal Papilloma Tissue J. Virol., February 1, 2002; 76(3): 1533 - 1536. [Abstract] [Full Text] [PDF]
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M. Narimatsu, H. Maeda, S. Itoh, T. Atsumi, T. Ohtani, K. Nishida, M. Itoh, D. Kamimura, S.-J. Park, K. Mizuno, et al. Tissue-Specific Autoregulation of the stat3 Gene and Its Role in Interleukin-6-Induced Survival Signals in T Cells Mol. Cell. Biol., October 1, 2001; 21(19): 6615 - 6625. [Abstract] [Full Text] [PDF]
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Z.-Q. Ning, J. Li, and R. J. Arceci Signal transducer and activator of transcription 3 activation is required for Asp816 mutant c-Kit-mediated cytokine-independent survival and proliferation in human leukemia cells Blood, June 1, 2001; 97(11): 3559 - 3567. [Abstract] [Full Text] [PDF]
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 J. Suter, I. R. Hendry, L. Ndjountche, K. Obholz, J. K. Pru, J. S. Davis, and B. R. Rueda Mediators of Interferon {{gamma}}-Initiated Signaling in Bovine Luteal Cells Biol Reprod, May 1, 2001; 64(5): 1481 - 1486. [Abstract] [Full Text]
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T. Alonzi, D. Maritano, B. Gorgoni, G. Rizzuto, C. Libert, and V. Poli Essential Role of STAT3 in the Control of the Acute-Phase Response as Revealed by Inducible Gene Activation in the Liver Mol. Cell. Biol., March 1, 2001; 21(5): 1621 - 1632. [Abstract] [Full Text]
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A. Suzuki, T. Hanada, K. Mitsuyama, T. Yoshida, S. Kamizono, T. Hoshino, M. Kubo, A. Yamashita, M. Okabe, K. Takeda, et al. Cis3/Socs3/Ssi3 Plays a Negative Regulatory Role in Stat3 Activation and Intestinal Inflammation J. Exp. Med., February 19, 2001; 193(4): 471 - 482. [Abstract] [Full Text] [PDF]
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Y. Shen, G. Devgan, J. E. Darnell Jr., and J. F. Bromberg Constitutively activated Stat3 protects fibroblasts from serum withdrawal and UV-induced apoptosis and antagonizes the proapoptotic effects of activated Stat1 PNAS, February 1, 2001; (2001) 41588198. [Abstract] [Full Text]
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J. Domen and I. L. Weissman Hematopoietic Stem Cells Need Two Signals to Prevent Apoptosis; Bcl-2 Can Provide One of These, Kitl/C-KIT Signaling the Other J. Exp. Med., December 18, 2000; 192(12): 1707 - 1718. [Abstract] [Full Text] [PDF]
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 R. M. GALLUCCI, P. P. SIMEONOVA, J. M. MATHESON, C. KOMMINENI, J. L. GURIEL, T. SUGAWARA, and M. I. LUSTER Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice FASEB J, December 1, 2000; 14(15): 2525 - 2531. [Abstract] [Full Text]
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A. S. K. de Hooge, F. A. J. van de Loo, O. J. Arntz, and W. B. van den Berg Involvement of IL-6, Apart from Its Role in Immunity, in Mediating a Chronic Response during Experimental Arthritis Am. J. Pathol., December 1, 2000; 157(6): 2081 - 2091. [Abstract] [Full Text] [PDF]
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S. T. Ahmed and L. B. Ivashkiv Inhibition of IL-6 and IL-10 Signaling and Stat Activation by Inflammatory and Stress Pathways J. Immunol., November 1, 2000; 165(9): 5227 - 5237. [Abstract] [Full Text] [PDF]
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G. Fantuzzi and R. Faggioni Leptin in the regulation of immunity, inflammation, and hematopoiesis J. Leukoc. Biol., October 1, 2000; 68(4): 437 - 446. [Abstract] [Full Text]
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C. Kawamura, M. Kizaki, K. Yamato, H. Uchida, Y. Fukuchi, Y. Hattori, T. Koseki, T. Nishihara, and Y. Ikeda Bone morphogenetic protein-2 induces apoptosis in human myeloma cells with modulation of STAT3 Blood, September 15, 2000; 96(6): 2005 - 2011. [Abstract] [Full Text] [PDF]
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M. Fujimoto, T. Naka, R. Nakagawa, Y. Kawazoe, Y. Morita, A. Tateishi, K. Okumura, M. Narazaki, and T. Kishimoto Defective Thymocyte Development and Perturbed Homeostasis of T cells in STAT-Induced STAT Inhibitor-1/Suppressors of Cytokine Signaling-1 Transgenic Mice J. Immunol., August 15, 2000; 165(4): 1799 - 1806. [Abstract] [Full Text] [PDF]
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S. Hess, H. Smola, U. Sandaradura de Silva, D. Hadaschik, D. Kube, S. E. Baldus, U. Flucke, and H. Pfister Loss of IL-6 Receptor Expression in Cervical Carcinoma Cells Inhibits Autocrine IL-6 Stimulation: Abrogation of Constitutive Monocyte Chemoattractant Protein-1 Production J. Immunol., August 15, 2000; 165(4): 1939 - 1948. [Abstract] [Full Text] [PDF]
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 K L STREETZ, T LUEDDE, M P MANNS, and C TRAUTWEIN Interleukin 6 and liver regeneration Gut, August 1, 2000; 47(2): 309 - 312. [Full Text] [PDF]
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D. DUVAL, B. REINHARDT, C. KEDINGER, and H. BOEUF Role of suppressors of cytokine signaling (Socs) in leukemia inhibitory factor (LIF) -dependent embryonic stem cell survival FASEB J, August 1, 2000; 14(11): 1577 - 1584. [Abstract] [Full Text]
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L. Rui, D. R. Gunter, J. Herrington, and C. Carter-Su Differential Binding to and Regulation of JAK2 by the SH2 Domain and N-Terminal Region of SH2-Bbeta Mol. Cell. Biol., May 1, 2000; 20(9): 3168 - 3177. [Abstract] [Full Text]
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E. S. Park, H. Kim, J. M. Suh, S. J. Park, S. H. You, H. K. Chung, K. W. Lee, O-Y. Kwon, B. Y. Cho, Y. K. Kim, et al. Involvement of JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) in the Thyrotropin Signaling Pathway Mol. Endocrinol., May 1, 2000; 14(5): 662 - 670. [Abstract] [Full Text]
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H. Daino, I. Matsumura, K. Takada, J. Odajima, H. Tanaka, S. Ueda, H. Shibayama, H. Ikeda, M. Hibi, T. Machii, et al. Induction of apoptosis by extracellular ubiquitin in human hematopoietic cells: possible involvement of STAT3 degradation by proteasome pathway in interleukin 6-dependent hematopoietic cells Blood, April 15, 2000; 95(8): 2577 - 2585. [Abstract] [Full Text] [PDF]
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J. R. Grandis, S. D. Drenning, Q. Zeng, S. C. Watkins, M. F. Melhem, S. Endo, D. E. Johnson, L. Huang, Y. He, and J. D. Kim Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo PNAS, April 11, 2000; 97(8): 4227 - 4232. [Abstract] [Full Text] [PDF]
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I. Kato, T. Miyazaki, T. Nakamura, and A. Kudo Inducible differentiation and apoptosis of the pre-B cell receptor-positive pre-B cell line Int. Immunol., March 1, 2000; 12(3): 325 - 334. [Abstract] [Full Text] [PDF]
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K. Suzuki, H. Nakajima, Y. Saito, T. Saito, W. J. Leonard, and I. Iwamoto Janus kinase 3 (Jak3) is essential for common cytokine receptor {gamma} chain ({gamma}c)-dependent signaling: comparative analysis of {gamma}c, Jak3, and {gamma}c and Jak3 double-deficient mice Int. Immunol., February 1, 2000; 12(2): 123 - 132. [Abstract] [Full Text] [PDF]
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M. Kieslinger, I. Woldman, R. Moriggl, J. Hofmann, J.-C. Marine, J. N. Ihle, H. Beug, and T. Decker Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation Genes & Dev., January 15, 2000; 14(2): 232 - 244. [Abstract] [Full Text]
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