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TGF-beta 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

AuthorsBotella, Luisa María CSIC ORCID ; Sanz-Rodriguez, Francisco; Komi, Yusuke; Fernandez-Lopez, Africa CSIC; Varela, Elisa; Garrido-Martin, Eva M. CSIC ORCID; Narla, Goutham; Friedman, Scott L.; Kojima, Soichi
KeywordsAlternative splicing
Growth regulation
Similar to mothers against decapentaplegic 3–specificity protein 1–Krüppel-like factor 6 interaction (Smad3–Sp1–KLF6 interaction)
Transforming growth factor-β (TGF-β)
Issue Date15-Apr-2009
PublisherPortland Press
CitationBiochemical Journal 419 (2) 485-495 (2009)
AbstractKLF6 (Krüppel-like factor 6) is a ranscription 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 lower-molecular-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, growth-suppressive 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, which may 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
Description13 p.-6 fig.-3 fig. supl.
Publisher version (URL)http://dx.doi.org/:10.1042/BJ20081434
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