Disease relevance of CTF1

• 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 [1].
• All pituitaries and pituitary adenomas expressed OSM transcripts, whereas no expression of CT-1 was found [2].
• Because other cytokines utilizing this receptor subunit stimulate acute-phase protein synthesis, we tested cardiotrophin-1 in in vitro assays of protein synthesis by primary rat hepatocytes, rat hepatoma cells (H35), and human hepatoma cells (HepG2) [3].
• Murine cardiotrophin-1 stimulates the acute-phase response in rat hepatocytes and H35 hepatoma cells [3].
• Although cardiac CT-1 gene expression is known to be upregulated in some animal models of congestive heart failure, the activation state of the CT-1 system in patients with congestive heart failure is unknown [4].

High impact information on CTF1

• Analysis of cDNA mutants expressed in E. coli and Drosophila cells reveals that the N-terminal portion of CTF-1 is sufficient for site-specific DNA recognition, protein dimerization, and adenovirus replication [5].
• Mutagenesis studies indicated that this domain is not the primary target of regulatory phosphorylations, suggesting that the growth factor may regulate a CTF-1-interacting protein [6].
• Prominent STAT3 phosphorylation in liver tissue was observed after IP plus I/R in normal mice but not in CT-1-null mice [7].
• Oxidative stress, a process involved in IP-induced hepatoprotection, was found to stimulate CT-1 release from isolated hepatocytes [7].
• Cardiotrophin-1 defends the liver against ischemia-reperfusion injury and mediates the protective effect of ischemic preconditioning [7].

Chemical compound and disease context of CTF1

• Using the hepatoma cell line HepG2, we report that the trans-activating function of the nuclear factor I/CCAAT box transcription factor (NFI/CTF-1) is, on the contrary, repressed by various stress conditions, including inflammatory cytokine treatment, glutathione depletion, heat and osmotic shocks, and chemical stress [8].

Biological context of CTF1

• 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 [1].
• In the present study we show that CT-1 activates its receptor expressed at the surface of a human neural cell line by recruiting gp130 and gp190/leukemia inhibitory factor receptor beta, as shown by analyzing their tyrosine phosphorylation level [9].
• 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 [1].
• 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 [1].
• The coding region of CT-1 is contained on three exons and is located on human chromosome 16p11.1-16p11.2 [10].

Anatomical context of CTF1

• Analysis of KB cell line culture supernatants after CT-1 treatment indicates that CT-1 stimulates the production of interleukin 6 (IL-6) in a time- and dose-dependent manner [11].
• In a search for novel factors that induce cardiac myocyte hypertrophy, cardiotrophin-1 (CT-1) was identified by coupling expression cloning with an embryonic stem cell-based model of cardiogenesis [12].
• 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 [1].
• Neutralizing antibody directed against gp130 and reconstitution experiments performed in the COS-7 cell line demonstrate that gp130-gp190 heterocomplex formation is essential for CT-1 signaling [9].
• CT-1 showed a dose-dependent induction of protein synthesis by primary rat hepatocytes, with effective concentrations ranging from 0.1 to 100 ng/ml [3].

Associations of CTF1 with chemical compounds

• Augmented expression of cardiotrophin-1 in failing human hearts is accompanied by diminished glycoprotein 130 receptor protein abundance [4].
• Transcriptional activation in yeast by the proline-rich activation domain of human CTF1 [13].
• We conclude that CT-1 is stable in specimens of whole blood treated with EDTA and aprotinin and stored for up to 48 hours at room temperature or on ice, hence permitting its development in the routine clinical investigation of patients with heart failure [14].
• Isolation and characterization of the murine cardiotrophin-1 gene: expression and norepinephrine-induced transcriptional activation [15].
• CT-1 increased c-fos and ANP expression (p<0.01) and cell area (p<0.01) in cardiomyocytes from both rat strains [16].

Physical interactions of CTF1

• METHODS AND RESULTS: This study was designed to determine left ventricular expression of CT-1 and its glycoprotein 130 (gp130)/leukemia inhibitory factor receptor complex in human end-stage heart failure due to ischemic and dilated cardiomyopathy [4].
• HOX11 was shown to interact in vitro and in vivo with CTF1 [17].
• Western immunoblot and supershift analysis shows that exogenously introduced CTF-1 proteins form different heterodimer complexes with the given subset of endogenous NFI proteins in epithelial or fibroblast cells [18].

Regulatory relationships of CTF1

• CTF1-enhanced TFIIB recruitment was observed in both human and yeast systems [19].
• Cardiotrophin-1 induces monocyte chemoattractant protein-1 synthesis in human umbilical vein endothelial cells [20].

Other interactions of CTF1

• The F284A mutation impaired the biological response induced by LIF and CT-1, whereas the response to OSM remained unchanged [21].
• This stimulation of IL-6 production by CT-1 is associated with an increase in intracellular levels of IL-6 mRNA [11].
• Genetic variants in the promoter (g983G>T) and coding region (A92T) of the human cardiotrophin-1 gene (CTF1) in patients with dilated cardiomyopathy [22].
• Cross-linking of iodinated CT-1 to the cell surface led to the identification of a third alpha component in addition to gp130 and gp190, with an apparent molecular mass of 80 kDa [9].
• Our results provide evidence that the CT-1 receptor is composed of a tripartite complex, a situation similar to the high affinity receptor for ciliary neurotrophic factor [9].

Analytical, diagnostic and therapeutic context of CTF1

• 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 [1].
• The RIA coupled with gel filtration chromatographic analyses showed that the major molecular form of circulating CT-1 corresponds to recombinant full-length human CT-1 [23].
• We therefore developed a competitive radioimmunoassay (RIA) for human CT-1 with rabbit antiserum recognizing the N-terminus region of human CT-1 and using recombinant human CT-1 as a calibrator [23].
• Immunohistochemistry confirmed the increased expression of CT-1 in cardiac myocytes [4].
• Novel neurotrophin-1/B cell-stimulating factor-3 (cardiotrophin-like cytokine) stimulates corticotroph function via a signal transducer and activator of transcription-dependent mechanism negatively regulated by suppressor of cytokine signaling-3 [24].

References