title: TGF-β signals the formation of a unique NF1/Smad4-dependent transcription repressor-complex in human diploid fibroblasts.
abstract: We earlier reported the formation of a unique nuclear NF1/Smad complex in serum-restricted fibroblasts that acts as an NF1-dependent repressor of the human adenine nucleotide translocase-2 gene (ANT2) [K. Luciakova, G. Kollarovic, P. Barath, B.D. Nelson, Growth-dependent repression of human adenine nucleotide translocator-2 (ANT2) transcription: evidence for the participation of Smad and Sp family proteins in the NF1-dependent repressor complex, Biochem. J. 412 (2008) 123-130]. In the present study, we show that TGF-β, like serum-restriction: (a) induces the formation of NF1/Smad repressor complexes, (b) increases binding of the complexes to the repressor elements (Go elements) in the ANT2 promoter, and (c) inhibits ANT2 expression. Repression of ANT2 by TGF-β is eliminated by mutating the NF1 binding sites in the Go repressor elements. All of the above responses to TGF-β are prevented by inhibitors of TGF-β RI and MAPK p38. These inhibitors also prevent NF1/Smad4 repressor complex formation and repression of ANT2 expression in serum-restricted cells, suggesting that similar signaling pathways are initiated by TGF-β and serum-restriction. The present finding that NF1/Smad4 repressor complexes are formed through TGF-β signaling pathways suggests a new, but much broader, role for these complexes in the initiation or maintenance of the growth-inhibited state.
authors.affiliation: Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Vlarska 7, 833 91 Bratislava, Slovak Republic. katarina.luciakova@savba.sk
authors.forename: Katarina
authors.initials: K
authors.lastname: Luciakova
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kollarovic
authors.forename: Miroslava
authors.initials: M
authors.lastname: Kretova
authors.forename: Ludmila
authors.initials: L
authors.lastname: Sabova
authors.forename: B Dean
authors.initials: BD
authors.lastname: Nelson
mesh_terms: D033742:Adenine Nucleotide Translocator 2 / Q000235:genetics*; D000818:Animals; D004171:Diploidy; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D025542:Neurofibromin 1 / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D051901:Smad4 Protein / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D033742:Adenine Nucleotide Translocator 2; D025542:Neurofibromin 1; D012097:Repressor Proteins; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta