RGD Reference Report - The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype. - Rat Genome Database

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The Ski-Zeb2-Meox2 pathway provides a novel mechanism for regulation of the cardiac myofibroblast phenotype.

Authors: Cunnington, Ryan H  Northcott, Josette M  Ghavami, Saeid  Filomeno, Krista L  Jahan, Fahmida  Kavosh, Morvarid S  Davies, Jared J L  Wigle, Jeffrey T  Dixon, Ian M C 
Citation: Cunnington RH, etal., J Cell Sci. 2014 Jan 1;127(Pt 1):40-9. doi: 10.1242/jcs.126722. Epub 2013 Oct 23.
RGD ID: 155882536
Pubmed: PMID:24155330   (View Abstract at PubMed)
DOI: DOI:10.1242/jcs.126722   (Journal Full-text)

Cardiac fibrosis is linked to fibroblast-to-myofibroblast phenoconversion and proliferation but the mechanisms underlying this are poorly understood. Ski is a negative regulator of TGF-β-Smad signaling in myofibroblasts, and might redirect the myofibroblast phenotype back to fibroblasts. Meox2 could alter TGF-β-mediated cellular processes and is repressed by Zeb2. Here, we investigated whether Ski diminishes the myofibroblast phenotype by de-repressing Meox2 expression and function through repression of Zeb2 expression. We show that expression of Meox1 and Meox2 mRNA and Meox2 protein is reduced during phenoconversion of fibroblasts to myofibroblasts. Overexpression of Meox2 shifts the myofibroblasts into fibroblasts, whereas the Meox2 DNA-binding mutant has no effect on myofibroblast phenotype. Overexpression of Ski partially restores Meox2 mRNA expression levels to those in cardiac fibroblasts. Expression of Zeb2 increased during phenoconversion and Ski overexpression reduces Zeb2 expression in first-passage myofibroblasts. Furthermore, expression of Meox2 is decreased in scar following myocardial infarction, whereas Zeb2 protein expression increases in the infarct scar. Thus Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by upregulating the expression of Meox2. This cascade might regulate cardiac myofibroblast phenotype and presents therapeutic options for treatment of cardiac fibrosis.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
MEOX2Humanmyocardial infarction  ISOMeox2 (Rattus norvegicus)protein:decreased expression:heart (rat)RGD 
Meox2Ratmyocardial infarction  IEP protein:decreased expression:heart (rat)RGD 
Meox2Mousemyocardial infarction  ISOMeox2 (Rattus norvegicus)protein:decreased expression:heart (rat)RGD 
ZEB2Humanmyocardial infarction  ISOZeb2 (Rattus norvegicus)protein:increased expression:heart (rat)RGD 
Zeb2Ratmyocardial infarction  IEP protein:increased expression:heart (rat)RGD 
Zeb2Mousemyocardial infarction  ISOZeb2 (Rattus norvegicus)protein:increased expression:heart (rat)RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Meox2Ratfibroblast proliferation  IMP  RGD 
Meox2Ratmyofibroblast differentiation  IEP  RGD 
Zeb2Ratmyofibroblast differentiation  IEP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Meox2  (mesenchyme homeobox 2)
Zeb2  (zinc finger E-box binding homeobox 2)

Genes (Mus musculus)
Meox2  (mesenchyme homeobox 2)
Zeb2  (zinc finger E-box binding homeobox 2)

Genes (Homo sapiens)
MEOX2  (mesenchyme homeobox 2)
ZEB2  (zinc finger E-box binding homeobox 2)


Additional Information