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

K C Wollert, T Taga, M Saito, M Narazaki, T Kishimoto, C C Glembotski, Ann Vernallis, J K Heath, D Pennica, W I Wood, K R Chien

Research output: Contribution to journalArticlepeer-review


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.
Original languageEnglish
Pages (from-to)9535-45
Number of pages11
JournalJournal of Biological Chemistry
Issue number16
Publication statusPublished - 19 Apr 1996

Bibliographical note

© 1996 by The American Society for Biochemistry and Molecular Biology, Inc.


  • 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


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