Activation of gp130 Transduces Hypertrophic Signals via STAT3 in Cardiac Myocytes

Kunisada, Keita; Tone, Eiroh; Fujio, Yasushi; Matsui, Hideo; Yamauchi–Takihara, Keiko; Kishimoto, Tadamitsu

doi:10.1161/01.cir.98.4.346

Cited by 215 publications

(159 citation statements)

References 44 publications

(39 reference statements)

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“…The construction of recombinant adenovirus/CMVdnStat3 Y705F (rAd/dnStat3) is described previously (Kunisada et al, 1998). DnStat3 was generated from Stat3 by changing the Tyr at position 705 into phenylalanine.…”

Section: Transduction Of Dominant-negative Stat3 Y705f In Cancer Cellsmentioning

confidence: 99%

Stat3 activation in human endometrial and cervical cancers

et al. 2007

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The activation of signal transducer and activator of transcription 3 (Stat3) has been implicated in the oncogenesis of cancer and is regarded as a novel target for cancer therapy. Stat3 is classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumour formation in nude mice. The constitutive activation of Stat3 has been frequently detected in various types of human cancers. However, the constitutive activation of Stat3 in endometrial and cervical cancers has not been studied. We examined tyrosine phosphorylation of Stat3 (activated form of Stat3) in multiple endometrial and cervical cancer tissues using tissue microarray slides as well as cancer cell lines to explore the possible activation of Stat3. Our results indicated that elevated phosphorylation of Stat3 was detected in cervical and endometrial cancer cell lines. Our results also showed that elevated levels of phosphorylation of Stat3 protein were detected in the endometrial and cervical cancer specimens. This is the first study to demonstrate that Stat3 is activated in human endometrial and cervical cancer tissues. Immunohistochemical staining showed that activated Stat3 is associated with increased expression of downstream antiapoptotic genes, Bcl-xL, survivin, and Mcl-1 in these tissues. Expression of a dominant-negative Stat3 mutant using adenovirus-mediated gene transfer inhibited cell growth and induced apoptosis in HeLa and SiHa cervical cancer cell lines expressing elevated levels of Stat3 phosphorylation. Further, a JAK/Stat3 small molecular inhibitor, JSI-124, induced apoptosis more selectively in HeLa and SiHa cancer cell lines than Ishikawa cell line without elevated levels of Stat3 phosphorylation. These results indicate that Stat3 is activated in human endometrial and cervical cancers and the inhibition of constitutive Stat3 signaling may be an effective target for cancer intervention in these two cancers.

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Section: Transduction Of Dominant-negative Stat3 Y705f In Cancer Cellsmentioning

confidence: 99%

Stat3 activation in human endometrial and cervical cancers

et al. 2007

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“…Further study showed that CT-1 caused both enhanced survival and hypertrophy of differentiated cardiac muscle cells and inhibited cardiac myocyte apoptosis after serum deprivation or cytokine stimulation (25,30,36,37,40). CT-1, acting through the gp130 receptor common to the IL-6 family, has been reported to be critical in the induction of hypertrophy in response to biomechanical overload and is overexpressed in cardiomyopathy, as part of a panel of "fetal" genes induced in response to damage (14,28).We have demonstrated that CT-1 is detected in abundance in freshly isolated and minced normal adult human lung and is expressed in both fetal and adult human primary cultured bronchial smooth muscle cells (HBSMC), predominantly in synthetic phenotypes. CT-1 induces a significant increase in HBSMC size, as judged by protein-to-DNA ratio and flow cytometry, and reduces the apoptosis induced both by serum deprivation and by Fas antibody/TNF-␣ treatment in HBSMC (38).…”

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Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

Zheng

Zhou

Seow

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants. Am J Physiol Lung Cell Mol Physiol 287: L1165-L1171, 2004. First published July 23, 2004 doi:10.1152/ ajplung.00171.2004.-Induction of hypertrophy and inhibition of apoptosis may be important mechanisms contributing to increased airway smooth muscle (ASM) mass in asthma. Data from our laboratory indicate that cardiotrophin-1 (CT-1) induces hypertrophy and inhibits apoptosis in isolated human ASM cells. To determine whether these novel effects of CT-1 also occur in the airway tissue milieu and to determine whether structural changes are accompanied by functional changes, matched pairs of guinea pig airway explants were treated with or without CT-1 for 7 days, and structural features as well as isometric and isotonic contractile and relaxant mechanical properties were measured. CT-1 (0.2-5 ng/ml) increased both myocyte mass and extracellular matrix in a concentration-dependent fashion. CT-1 (10 ng/ml)-treated tissues exhibited a significant increase in passive tension at all lengths on day 7; at optimal length, passive tension generated by CT-1-treated tissues was 1.72 Ϯ 0.12 vs. 1.0 Ϯ 0.1 g for control. Maximal isometric stress was decreased in the CT-1-treated group on day 7 (0.39 Ϯ 0.10 kg/cm 2 ) vs. control (0.77 Ϯ 0.15 kg/cm 2 , P Ͻ 0.05). Isoproterenol-induced relaxant potency was reduced in CT-1-treated tissues, log EC50 being Ϫ7.28 Ϯ 0.34 vs. Ϫ8.12 Ϯ 0.25 M in control, P Ͻ 0.05. These data indicate that CT-1 alters ASM structural and mechanical properties in the tissue environment and suggest that structural changes found in the airway wall in asthma are not necessarily associated with increased responsiveness. tracheal explants; mechanics; cytokines; asthma; matrix; smooth muscle hypertrophy INCREASED SMOOTH MUSCLE MASS has been repeatedly documented in asthmatic subjects (3,11,29,33,34), but the mechanisms responsible for the increased mass are unclear. The amount of both airway smooth muscle (ASM) and smooth muscle-associated matrix is greater with increased duration of asthma and may be an important determinant of the severity of airway responsiveness (3,15). Yet the functional alterations in ASM in asthma are uncertain (29, 34). When bronchial segments from asthmatics have been studied in vitro, the majority of studies have shown no change in mechanical properties, although isolated cells from asthmatics show a higher velocity of shortening (16). Tracheal tissue offers some advantages in studies of ASM behavior in that the muscle is more uniform in orientation, and less matrix elements are present. The only study of asthmatic trachea, in severe asthma, showed a nonspecific increase in force generation, suggesting increased contractility. However, force was normalized to tissue weight, not muscle mass (1); thus, the changes could have been a reflection of increased muscle.Cardiotrophin-1 (CT-1), a member of the IL-6 family, was initially defined as a factor that has the capacity to induce cardiac myocyt...

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“…These cytokines prevent apoptosis and stimulate cardiac hypertrophy in a manner essentially indistinguishable from the actions of CT-1. All three cytokines stimulate myocyte hypertrophy through activation of the Jak-STAT (Signal Transducers and Activators of Transcription) pathway, and prevent apoptosis through activation of ERK1/2 (Extracellular signal Regulated protein Kinases 1 & 2) and the phosphatidylinositol 3-OH kinase (PI3 kinase)/ Akt pathways [7][8][9][40][41][42][43][44]. LIF is elevated to a greater degree after infarct in mice lacking IL-6 compared to wild type mice [42], and we expected that one or both of these cytokines would be elevated to a greater extent after ischemia-reperfusion in CT-1 −/− mice than in control mice.…”

Section: Discussionmentioning

confidence: 99%

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

et al. 2006

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Cardiotrophin-1 (CT-1) was identified as a growth factor for cardiac myocytes, and CT-1 protects myocytes from cell death. Adult CT-1−/− mice exhibit neural deficits including the loss of preganglionic sympathetic neurons, but their autonomic and cardiac parameters have not been examined. We used these mice to determine if the absence of CT-1 or loss of preganglionic sympathetic input altered heart rate, left ventricular pressure, cardiac contractility (dP/dt), or cell death following ischemia-reperfusion. Basal heart rate was increased in CT-1−/− mice, and this difference was abolished by ganglionic block. Left ventricular pressure and dP/dt were unchanged. Dobutamine stimulated similar increases in heart rate and dP/dt in both genotypes, but ventricular pressure was significantly lower in CT-1 nulls. Cardiac expression of interleukin-6 (IL-6) mRNA was increased significantly in CT-1 null mice, while leukemia inhibitory factor (LIF) mRNA was unchanged. Infarct size normalized to area at risk was no different in CT-1 −/− mice (33.8±1.0 % vs. 37.7±3.2 % WT) 24 hours after ischemia-reperfusion. Induction of IL-6 mRNA after infarct was significantly abrogated in CT-1 null mice compared to wild type mice, but LIF mRNA induction remained significant in CT-1 null mice and might contribute to cardiac protection in the absence of CT-1.

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Activation of gp130 Transduces Hypertrophic Signals via STAT3 in Cardiac Myocytes

Cited by 215 publications

References 44 publications

Stat3 activation in human endometrial and cervical cancers

Stat3 activation in human endometrial and cervical cancers

Cardiotrophin-1 alters airway smooth muscle structure and mechanical properties in airway explants

The lack of cardiotrophin-1 alters expression of interleukin-6 and leukemia inhibitory factor mRNA but does not impair cardiac injury response

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