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

Luisa M. Botella, Francisco Sanz-Rodriguez, Yusuke Komi, Africa Fernandez-L., Elisa Varela, Eva M. Garrido-Martin, Goutham Narla, Scott L. Friedman, Soichi Kojima

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)485-495
Number of pages11
JournalBiochemical Journal
Volume419
Issue number2
DOIs
StatePublished - 15 Apr 2009

Keywords

  • 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)

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