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 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.
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Research Article|
March 27 2009
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
;
Luisa M. Botella
1
*Centro de Investigaciones Biológicas, CSIC (Consejo Superior de Investigaciones Científicas), 28040 Madrid, Spain
1To whom correspondence should be addressed (email cibluisa@cib.csic.es).
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Francisco Sanz-Rodriguez
;
Francisco Sanz-Rodriguez
†Departamento de Biología y Genética, Universidad Autónoma Madrid, 28049 Madrid, Spain
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Yusuke Komi
;
Yusuke Komi
‡Molecular Ligand Research Team, Chemical Genomics Research Group, Chemical Biology Department, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan
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Africa Fernandez-L
;
Africa Fernandez-L
§Sloan Kettering Cancer Center, New York, NY 10065-1275, U.S.A.
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Elisa Varela
;
Elisa Varela
¶FMI Institute, 4058 Basel, Switzerland
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Eva M. Garrido-Martin
;
Eva M. Garrido-Martin
*Centro de Investigaciones Biológicas, CSIC (Consejo Superior de Investigaciones Científicas), 28040 Madrid, Spain
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Goutham Narla
;
Goutham Narla
∥Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029-6574, U.S.A.
**Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029-6574, U.S.A.
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Scott L. Friedman
;
Scott L. Friedman
††Liver Diseases, Mount Sinai School of Medicine, New York, NY 10029-6574, U.S.A.
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Soichi Kojima
Soichi Kojima
‡Molecular Ligand Research Team, Chemical Genomics Research Group, Chemical Biology Department, RIKEN Advanced Science Institute, Wako, Saitama 351-0198, Japan
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Biochem J (2009) 419 (2): 485–495.
Article history
Received:
July 15 2008
Revision Received:
December 05 2008
Accepted:
December 10 2008
Accepted Manuscript online:
December 10 2008
Citation
Luisa M. Botella, Francisco Sanz-Rodriguez, Yusuke Komi, Africa Fernandez-L, Elisa Varela, Eva M. Garrido-Martin, Goutham Narla, Scott L. Friedman, Soichi Kojima; 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. Biochem J 15 April 2009; 419 (2): 485–495. doi: https://doi.org/10.1042/BJ20081434
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