Wollert, K C, Taga, T, Saito, M, Narazaki, M, Kishimoto, T, Glembotski, C C, Vernallis, Ann, Heath, J K, Pennica, D, Wood, W I and Chien, K R (1996). Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways. Journal of Biological Chemistry, 271 (16), pp. 9535-45.
Abstract
Cardiotrophin-1 (CT-1) was recently isolated by expression cloning based on its ability to induce an increase in cell size in neonatal rat ventricular cardiomyocytes. Sequence similarity data suggested that CT-1 is a novel member of a family of structurally related cytokines sharing the receptor component gp130. The present study documents that gp130 is required for CT-1 signaling in cardiomyocytes, by demonstrating that a monoclonal anti-gp130 antibody completely inhibits c-fos induction by CT-1. Similarly, a leukemia inhibitory factor receptor subunit beta (LIFRbeta) antagonist effectively blocks the CT-1 induction of c-fos, indicating a requirement for LIFRbeta in the hypertrophic response, as well. Upon stimulation with CT-1, both gpl30 and the LIFRbeta are tyrosine-phosphorylated, providing further evidence that CT-1 signals through the gp130/LIFRbeta heterodimer in cardiomyocytes. CT-1 induces a hypertrophic response in cardiomyocytes that is distinct from the phenotype seen after alpha-adrenergic stimulation, both with regard to cell morphology and gene expression pattern. Stimulation with CT-1 results in an increase in cardiac cell size that is characterized by an increase in cell length but no significant change in cell width. Confocal laser microscopy of CT-1 stimulated cells reveals the assembly of sarcomeric units in series rather than in parallel, as seen after alpha-adrenergic stimulation. CT-1 induces a distinct pattern of immediate early genes, and up-regulates the atrial natriuretic factor (ANF) gene, but does not affect skeletal alpha-actin or myosin light chain-2v expression. As evidenced by nuclear run-on transcription assays, both CT-1 and alpha-adrenergic stimulation lead to an increase in ANF gene transcription. Transient transfection analyses document that, in contrast to alpha-adrenergic stimulation, the CT-1 responsive cis-regulatory elements are located outside of the proximal 3 kilobase pairs of the ANF 5'-flanking region. These studies indicate that CT-1 can activate a distinct form of myocardial cell hypertrophy, characterized by the promotion of sarcomere assembly in series, via gpl30/LIFRbeta-dependent signaling pathways.
Publication DOI: | https://doi.org/10.1074/jbc.271.16.9535 |
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Divisions: | College of Health & Life Sciences > School of Biosciences > Cell & Tissue Biomedical Research College of Health & Life Sciences > Chronic and Communicable Conditions College of Health & Life Sciences College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine College of Health & Life Sciences > School of Biosciences |
Additional Information: | © 1996 by The American Society for Biochemistry and Molecular Biology, Inc. |
Uncontrolled Keywords: | Actins,Animals,Atrial Natriuretic Factor,Cells, Cultured,Ciliary Neurotrophic Factor,Cytokines,Gene Expression,Genes, fos,Growth Inhibitors,Heart,Humans,Interleukin-6,Leukemia Inhibitory Factor,Leukemia Inhibitory Factor Receptor alpha Subunit,Lymphokines,Mice,Myocardium,Nerve Growth Factors,Nerve Tissue Proteins,Proto-Oncogene Proteins c-fos,Receptors, Cytokine,Receptors, OSM-LIF,Recombinant Fusion Proteins,Sarcomeres,Signal Transduction,Transfection |
Publication ISSN: | 1083-351X |
Last Modified: | 29 Oct 2024 12:42 |
Date Deposited: | 20 Mar 2019 09:35 |
Full Text Link: | |
Related URLs: |
http://www.jbc. ... ent/271/16/9535
(Publisher URL) |
PURE Output Type: | Article |
Published Date: | 1996-04-19 |
Authors: |
Wollert, K C
Taga, T Saito, M Narazaki, M Kishimoto, T Glembotski, C C Vernallis, Ann Heath, J K Pennica, D Wood, W I Chien, K R |