Identification of NF-kappaB responsive elements in follistatin related gene (FLRG) promoter.
Follistatin related gene (FLRG) has been previously identified from a chromosomal translocation observed in a B-cell chronic lymphocytic leukemia (B-CLL). FLRG (alternative names: follistatin-related protein, FSRP/follistatin-like-3, FSTL3) is a secreted glycoprotein highly similar to follistatin. Like follistatin, FLRG is involved in the regulation of various biological effects through its binding to members of the transforming growth factor beta (TGFbeta) superfamily such as activin A and myostatin. We have previously shown that TGFbeta and activin A are potent inducers of FLRG transcriptional activation through the Smad proteins. Using a biochemical approach, we investigated whether tumor necrosis factor alpha (TNFalpha) could regulate FLRG expression since TNFalpha plays a critical role in hematopoietic malignancies. We demonstrate that TNFalpha activates FLRG expression at the transcriptional level. This activation depends on a promoter region containing four 107-108 bp DNA repeats, which are evolutionary conserved in primates. These repeats carry a strong phylogenetic signal, which is not common among non-coding sequences. Each DNA repeat contains one TNFalpha responsive element (5'-GGGAGAG/TTCC-3') able to bind nuclear factor kappaB (NF-kappaB) transcription factors. We also show that TGFbeta, through the Smad proteins, potentates the effect of TNFalpha on FLRG expression. This cooperation is unexpected since TGFbeta and TNFalpha usually have opposite biological effects. In all, this work brings new insights in the understanding of FLRG regulation by cytokines and growth factors. It opens attractive perspectives of research that should allow us to better understand the role of FLRG during tumorigenesis.
Bartholin
Laurent
L
Inserm, U590, IFR62, Lyon, F-69008, France. bartholi@lyon.fnclcc.fr
Guindon
Stéphane
S
Martel
Sylvie
S
Corbo
Laura
L
Rimokh
Ruth
R
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D019143:Evolution, Molecular; D038702:Follistatin-Related Proteins / Q000235:genetics*; D006801:Humans; D008907:Mink; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D020218:Response Elements / Q000235:genetics*; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
D038702:Follistatin-Related Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha