We described recently the activation of the Janus kinasesignal transducer and activator of transcription (JakSTAT) and mitogen-activated protein (MAP) kinase pathways by leukemia inhibitory factor (LIF) through gp130, a signal transducer of IL-6-related cytokines, that transduces hypertrophic signals in cardiac myocytes. In addition, stimulation of gp130 by IL-6-related cytokines is known to exert a cytoprotective effect. In the present study, we investigated the possibility that activation of gp130 initiates activation of the cytoprotective genes in cardiac myocytes. Incubation of cardiac myocytes with LIF induced the expression of bcl-x, and the isoform that was induced by LIF was identified as bcl-xL. Induction of bcl-xL protein was also identified by Western blotting. Antisense oligonucleotide against bcl-x mRNA inhibited protective effect of LIF accompanied with the reduction in bclxL protein. We constructed bcl-x promoter-luciferase reporter gene plasmids (-639/+10- or -161/+10-luciferase), and transfected them to cardiac myocytes. LIF stimulation increased the luciferase activity of -639/+10-luciferase plasmids. Although -161/+10-luciferase plasmids presented comparable responsiveness to LIF, the basal transcription level was impaired. The LIF-responsive cis-element was localized to a DNA fragment (positions -161 to +10) that contains an interferon-gamma activation site (GAS) motif (GGA) at position -41 of the bcl-x gene promoter. This motif bound to STAT1, not to STAT3, and site-directed mutagenesis revealed that this motif was essential for LIF-responsive promoter activity. These data suggest that LIF induces bcl-x mRNA via STAT1 binding cis-element in cardiac myocytes, presenting cytoprotective effect.
Y Fujio, K Kunisada, H Hirota, K Yamauchi-Takihara, T Kishimoto
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2003 | |
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Promoter Choice Influences Alternative Splicing and Determines the Balance of Isoforms Expressed from the Mouse bcl-X Gene
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The Journal of biological chemistry | 2001 |
Thrombopoietin Regulates Bcl-xL Gene Expression through Stat5 and Phosphatidylinositol 3-Kinase Activation Pathways
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Factors Secreted by Human Neuroblastoma Mediate Doxorubicin Resistance by Activating STAT3 and Inhibiting Apoptosis
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2001 | |
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The EMBO Journal | 2000 |
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Proceedings of the National Academy of Sciences | 2000 |
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Identification and Characterization of Nuclear Factor κB Binding Sites in the Murine bcl-χ Promoter
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Cytokines and their receptors in cardiovascular diseases — role of gp130 signalling pathway in cardiac myocyte growth and maintenance
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Journal of Molecular and Cellular Cardiology | 2000 |
Rheumatoid arthritis synovial stromal cells inhibit apoptosis and up-regulate Bcl-xL expression by B cells in a CD49/CD29-CD106-dependent mechanism
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Journal of immunology (Baltimore, Md. : 1950) | 2000 |
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Journal of Molecular and Cellular Cardiology | 2000 |
La vía JAK-STAT de señalización intracelular y su repercusión en oncogénesis, inmunomodulación y desarrollo
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Ischemia-induced STAT-1 Expression and Activation Play a Critical Role in Cardiomyocyte Apoptosis
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The Journal of biological chemistry | 2000 |
DNA Binding Specificity of Different STAT Proteins: COMPARISON OF IN VITRO SPECIFICITY WITH NATURAL TARGET SITES
GB Ehret, P Reichenbach, U Schindler, CM Horvath, S Fritz, M Nabholz, P Bucher |
The Journal of biological chemistry | 2000 |
Effects of Protease Inhibitors and Antioxidants on In Vitro Survival of Porcine Primordial Germ Cells1
CK Lee, RL Weaks, GA Johnson, FW Bazer, JA Piedrahita |
Biology of reproduction | 2000 |
Control of myeloid differentiation and survival by Stats
TE Smithgall, SD Briggs, S Schreiner, EC Lerner, H Cheng, MB Wilson |
Oncogene | 2000 |
Cooperation between STAT5 and phosphatidylinositol 3-kinase in the IL-3-dependent survival of a bone marrow derived cell line
SC Santos, S Dumon, P Mayeux, S Gisselbrecht, F Gouilleux |
Oncogene | 2000 |
Signal Transducer and Activator of Transcription 3 Is Required for Glycoprotein 130-mediated Induction of Vascular Endothelial Growth Factor in Cardiac Myocytes
M Funamoto, Y Fujio, K Kunisada, S Negoro, E Tone, T Osugi, H Hirota, M Izumi, K Yoshizaki, K Walsh, T Kishimoto, K Yamauchi-Takihara |
The Journal of biological chemistry | 2000 |
From Molecule to Men
M Zehender, H Just, G Breithardt |
2000 | |
Apoptosis in Cardiac Biology
H Schunkert, GA Riegger |
2000 | |
The Hypertrophied Heart
N Takeda, M Nagano, NS Dhalla |
2000 | |
Leukemia-Inhibitory Factor—Neuroimmune Modulator of Endocrine Function*
CJ Auernhammer, S Melmed |
Endocrine reviews | 2000 |
The Rel/NF-κB Family Directly Activates Expression of the Apoptosis Inhibitor Bcl-x L
C Chen, LC Edelstein, C Gélinas |
Molecular and cellular biology | 2000 |
Decrease Tyrosine Phosphorylation of Stat3 in Human Myocardium with End-Stage Congestive Heart Failure
C Wei, JS McLaughlin |
Microscopy and Microanalysis | 2000 |
Ectopic expression of fibroblast growth factor receptor 3 promotes myeloma cell proliferation and prevents apoptosis
EE Plowright, Z Li, PL Bergsagel, M Chesi, DL Barber, DR Branch, RG Hawley, AK Stewart |
Blood | 2000 |
Akt promotes survival of cardiomyocytes in vitro and protects against ischemia-reperfusion injury in mouse heart.
Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K |
Circulation | 2000 |
STAT signaling in the pathogenesis and treatment of cancer
DA Frank |
Molecular Medicine | 1999 |
Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling
N Farrelly, YJ Lee, J Oliver, C Dive, CH Streuli |
The Journal of Cell Biology | 1999 |
Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein
L Gabriele, J Phung, J Fukumoto, D Segal, IM Wang, P Giannakakou, NA Giese, K Ozato, HC 3rd |
Journal of Experimental Medicine | 1999 |
Is apoptosis an important pathogenic factor in cardiovascular disease?
Aukrust, Gullestad, Froland |
European Journal of Clinical Investigation | 1999 |
Constitutive Activation of Stat3 Signaling Confers Resistance to Apoptosis in Human U266 Myeloma Cells
R Catlett-Falcone, TH Landowski, MM Oshiro, J Turkson, A Levitzki, R Savino, G Ciliberto, L Moscinski, JL Fernández-Luna, G Nuñez, WS Dalton, R Jove |
Immunity | 1999 |
Signalling through the JAK–STAT pathway in the developing brain
E Cattaneo, L Conti, C De-Fraja |
Trends in Neurosciences | 1999 |
Fetal Anemia and Apoptosis of Red Cell Progenitors in Stat5a−/−5b−/− Mice
M Socolovsky, AE Fallon, S Wang, C Brugnara, HF Lodish |
Cell | 1999 |
Regulation of Apoptosis in Myeloid Cells by Interferon Consensus Sequence-Binding Protein
L Gabriele, J Phung, J Fukumoto, D Segal, IM Wang, P Giannakakou, NA Giese, K Ozato, HC Morse |
Journal of Experimental Medicine | 1999 |
The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes
S Bialik, VL Cryns, A Drincic, S Miyata, AL Wollowick, A Srinivasan, RN Kitsis |
Circulation research | 1999 |
Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions
M Gwechenberger, LH Mendoza, KA Youker, NG Frangogiannis, CW Smith, LH Michael, ML Entman |
Circulation | 1999 |
IL-3 dependent regulation of Bcl-xL gene expression by STAT5 in a bone marrow derived cell line
S Dumon, SC Santos, F Debierre-Grockiego, V Gouilleux-Gruart, L Cocault, C Boucheron, P Mollat, S Gisselbrecht, F Gouilleux |
Oncogene | 1999 |
Erythropoietin Can Induce the Expression of Bcl-x L through Stat5 in Erythropoietin-dependent Progenitor Cell Lines
M Silva, A Benito, C Sanz, F Prosper, D Ekhterae, G Nuñez, JL Fernandez-Luna |
The Journal of biological chemistry | 1999 |
Mast Cells Cause Apoptosis of Cardiomyocytes and Proliferation of Other Intramyocardial Cells In Vitro
M Hara, A Matsumori, K Ono, H Kido, MW Hwang, T Miyamoto, A Iwasaki, M Okada, K Nakatani, S Sasayama |
Circulation | 1999 |
Characterization of Insulin-Like Growth Factor-1–Induced Activation of the JAK/STAT Pathway in Rat Cardiomyocytes
T Takahashi, K Fukuda, J Pan, H Kodama, M Sano, S Makino, T Kato, T Manabe, S Ogawa |
Circulation research | 1999 |
Inhibition of Bcl-xL expression sensitizes normal human keratinocytes and epithelial cells to apoptotic stimuli
JK Taylor, QQ Zhang, BP Monia, EG Marcusson, NM Dean |
Oncogene | 1999 |
Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway
PC Heinrich, I Behrmann, G Müller-Newen, F Schaper, L Graeve |
Biochemical Journal | 1998 |
STAT3 mediates the survival signal in oncogenicras-transfected intestinal epithelial cells
S Zushi, Y Shinomura, T Kiyohara, Y Miyazaki, S Kondo, M Sugimachi, Y Higashimoto, S Kanayama, Y Matsuzawa |
International Journal of Cancer | 1998 |
Generation of a novel stem cell factor-dependent mast cell progenitor
A Masuda, T Matsuguchi, K Yamaki, T Hayakawa, Y Yoshikai |
Journal of immunology (Baltimore, Md. : 1950) | 1998 |
Activation of Phosphatidylinositol 3-Kinase through Glycoprotein 130 Induces Protein Kinase B and p70 S6 Kinase Phosphorylation in Cardiac Myocytes
H Oh, Y Fujio, K Kunisada, H Hirota, H Matsui, T Kishimoto, K Yamauchi-Takihara |
The Journal of biological chemistry | 1998 |
Tyrosine 1101 of Tie2 Is the Major Site of Association of p85 and Is Required for Activation of Phosphatidylinositol 3-Kinase and Akt
CD Kontos, TP Stauffer, WP Yang, JD York, L Huang, MA Blanar, T Meyer, KG Peters |
Molecular and cellular biology | 1998 |