TGF-β regulates expression of KLF6 and its splice variants, and promotes cooperative transactivation of common target genes through a Smad3/Sp1/KLF6 interaction

Luisa M Botella (1) , Francisco Sanz-Rodriguez , Yusuke Komi , Africa Fernandez-L , Elisa Varela , Eva M Garrido-Martin , Goutham Narla , Scott L Friedman , Soichi Kojima

1 Cellular and Molecular Human Physiopathology

KLF6 is a transcription factor and tumor suppressor with a growing range of biological activities and transcriptional targets. Among these, KLF6 suppresses growth through transactivation of transforming growth factor-β1. KLF6 can be alternatively spliced, generating lower molecular weight isoforms that antagonize the full-length, 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 cooperation between KLF6 and Sp1. Using co-transfection, co-immunoprecipitation and FRET, our data demonstrate that KLF6 cooperates with Sp1 in transcriptionally regulating KLF6-responsive genes, and that this cooperation 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. Second, KLF6/Sp1 cooperation is further enhanced by the TGF-β/Smad pathway via the likely formation of a tripartite complex of KLF6, Sp1, and Smad3 in which KLF6 interacts indirectly with Smad3 through Sp1, which may serve as a bridging molecule to coordinate this interaction. These findings unveil a finely tuned network of interactions between KLF6, Sp1, and TGF-β to regulate target genes.

Mots clés: Life Sciences

Luisa M Botella, Francisco Sanz-Rodriguez, Yusuke Komi, Africa Fernandez-L, Elisa Varela, et al.. TGF-β regulates expression of KLF6 and its splice variants, and promotes cooperative transactivation of common target genes through a Smad3/Sp1/KLF6 interaction. Biochemical Journal, 2009, 419 (2), pp.485-495. ⟨10.1042/BJ20081434⟩. ⟨hal-00479069⟩