Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1)

We have isolated the rat, mouse and human genes of a distant member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage inhibitin g cytokine-l (GDF-15/MIC-1) by screening of genomic libraries. All three ge nes are composed of two exons, and contain one single intron that interrupt s the coding sequences at identical positions within the prepro-domain of t he corresponding proteins. The predicted proteins contain the structural ha llmarks of members of the TGF-beta superfamily, including the seven conserv ed carboxy-terminal cysteine residues that form the cystine knot. The ortho logous molecules show the lowest sequence conservation of all members of th e TGF-beta superfamily. RT-PCR reveals an abundant expression of GDF-15/MIC -1 mRNA in numerous embryonic and adult organs and tissues. Promoter analys is of the rat promoter indicates the presence of multiple regulatory elemen ts, including a TATA-like sequence as well as several SP1, AP-1 and AP-2 si tes. Deletion analysis suggests that a 350 bp region upstream of the start of the open reading frame appears to be the most important for regulation o f transcription. (C) 1999 Elsevier Science B.V. All rights reserved.