RGD Reference Report - Gut-enriched Kruppel-like factor interaction with Smad3 inhibits myofibroblast differentiation. - Rat Genome Database

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Gut-enriched Kruppel-like factor interaction with Smad3 inhibits myofibroblast differentiation.

Authors: Hu, B  Wu, Z  Liu, T  Ullenbruch, MR  Jin, H  Phan, SH 
Citation: Hu B, etal., Am J Respir Cell Mol Biol. 2007 Jan;36(1):78-84. Epub 2006 Jul 20.
RGD ID: 2300420
Pubmed: PMID:16858008   (View Abstract at PubMed)
PMCID: PMC1899300   (View Article at PubMed Central)
DOI: DOI:10.1165/rcmb.2006-0043OC   (Journal Full-text)

Gut-enriched Kruppel-like factor (GKLF) has been reported to partially inhibit alpha-smooth muscle actin (alpha-SMA) gene transcription by competing for binding to the TGF-beta control element (TCE) with known activators such as Sp1 and other Kruppel-like factors. This incomplete inhibition via the TCE suggests an additional mechanism, which was evaluated in this study. The results showed that an alpha-SMA promoter mutated in the TCE remained susceptible to inhibition by GKLF in rat lung fibroblasts consistent with the existence of an additional TCE-independent mechanism. Since TGF-beta- induced alpha-SMA expression is Smad3-dependent, potential interaction between GKLF and Smad3 was examined as a basis for this additional inhibitory mechanism. Co-immunoprecipitation and yeast two-hybrid assays revealed that GKLF could bind Smad3 through the Smad3 MH2 domain. Electrophoretic mobility shift assays and ChIP assay indicated that this GKLF-Smad3 interaction inhibited Smad3 binding to the Smad3-binding element (SBE) in the alpha-SMA promoter, and the activity of an SBE containing artificial promoter. Further analysis using smad3(-/-) fibroblasts confirmed that the TCE-independent inhibition by GKLF was dependent on Smad3. These data taken together suggest that in addition to inhibition via the TCE, GKLF represses alpha-SMA gene expression by interacting with Smad3 to prevent Smad3 binding to the SBE. It represents the first evidence to directly link GKLF with Smad3, a key intracellular mediator of TGF-beta signaling, which should lead to a clearer understanding of the mechanism of how GKLF regulates TGF-beta-induced gene expression.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
transcription factor binding  IDA 2300420recombinant Klf4 and unknown speciesRGD 

Objects Annotated

Genes (Rattus norvegicus)
Smad3  (SMAD family member 3)


Additional Information