TGF-β regulates the expression of transcription factor KLF6 and its splice variants and promotes co-operative transactivation of common target genes through a Smad3-Sp1-KLF6 interaction Journal Article
| Authors: | Botella, L. M.; Sanz-Rodriguez, F.; Komi, Y.; Fernandez-L, A.; Varela, E.; Garrido-Martin, E. M.; Narla, G.; Friedman, S. L.; Kojima, S. |
| Article Title: | TGF-β regulates the expression of transcription factor KLF6 and its splice variants and promotes co-operative transactivation of common target genes through a Smad3-Sp1-KLF6 interaction |
| Abstract: | KLF6 (Krüppel-like factor 6) is a transcription factor and tumour suppressor with a growing range of biological activities and transcriptional targets. Among these, KLF6 suppresses growth through transactivation of TGF-β1 (transforming growth factor-β1). KLF6 can be alternatively spliced, generating lowermolecular-mass isoforms that antagonize the full-length WT (wild-type) protein and promote growth. A key target gene of full-length KLF6 is endoglin, which is induced in vascular injury. Endoglin, a homodimeric cell membrane glycoprotein and TGF-β auxiliary receptor, has a pro-angiogenic role in endothelial cells and is also involved in malignant progression. The aim of the present work was to explore the effect of TGF-β on KLF6 expression and splicing, and to define the contribution of TGF-β on promoters regulated by co-operation between KLF6 and Sp1 (specificity protein 1). Using co-transfection, co-immunoprecipitation and fluorescence resonance energy transfer, our data demonstrate that KLF6 co-operates with Sp1 in transcriptionally regulating KLF6-responsive genes and that this co-operation is further enhanced by TGF-β1 through at least two mechanisms. First, in specific cell types, TGF-β1 may decrease KLF6 alternative splicing, resulting in a net increase in full-length, growthsuppressive KLF6 activity. Secondly, KLF6-Sp1 co-operation is further enhanced by the TGF-β-Smad (similar to mothers against decapentaplegic) pathway via the likely formation of a tripartite KLF6-Sp1-Smad3 complex in which KLF6 interacts indirectly with Smad3 through Sp1, whichmay serve as a bridging molecule to co-ordinate this interaction. These findings unveil a finely tuned network of interactions between KLF6, Sp1 and TGF-β to regulate target genes. © The Authors Journal compilation. |
| Keywords: | controlled study; oncoprotein; human cell; genetics; proto-oncogene proteins; cancer growth; nonhuman; flow cytometry; polymerase chain reaction; protein function; animal cell; animal; cytology; metabolism; animals; gene targeting; complex formation; genes; smad3 protein; transforming growth factor beta; embryo; protein protein interaction; fluorescence; cell line; protein binding; hela cell; hela cells; angiogenesis; cercopithecus aethiops; cos cells; wild type; physiology; cell type; transcription factors; endothelium cell; endothelial cells; gene expression regulation; gene activation; protein processing; transcription regulation; targets; tumors; nucleic acids; alternative splicing; endoglin; growth regulation; similar to mothers against decapentaplegic 3-specificity protein 1-krüpel-like factor 6 interaction (smad3-sp1-klf6 interaction; transactivation; transforming growth factor-β (tgf-β); biological activities; cell types; co-immunoprecipitation; co-transfection; decapentaplegic; fluorescence resonance energy transfer; isoforms; malignant progression; specificity protein 1; splice variants; target genes; transcriptional targets; transforming growth factors; tumour suppressor; vascular injury; wild types; bioactivity; cell membranes; energy transfer; peptides; transcription; collagen; glutathione transferase; kruppel like factor 6; transcription factor sp1; klf6 protein, human; kruppel like factor; smad3 protein, human; alternative rna splicing; blood vessel injury; immunoprecipitation; plasmid; cell strain cos1; cercopithecus; kruppel-like transcription factors; sp1 transcription factor |
| Journal Title: | Biochemical Journal |
| Volume: | 419 |
| Issue: | 2 |
| ISSN: | 0264-6021 |
| Publisher: | Portland Press Ltd |
| Date Published: | 2009-04-15 |
| Start Page: | 485 |
| End Page: | 495 |
| Language: | English |
| DOI: | 10.1042/bj20081434 |
| PUBMED: | 19076057 |
| PROVIDER: | scopus |
| PMCID: | PMC2882110 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 1" - "Export Date: 30 November 2010" - "CODEN: BIJOA" - "Source: Scopus" |
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