GDF15 (growth differentiation factor 15)

Note	In the genome, the GDF15 gene is localized on chromosome 19 in the region p13.1-13.2. The macrophage inhibitory cytokine (MIC-1) DNA sequence is 2,746 bp long and consists of two exons separated by an intron. A conserved TATA-like motif (TATAAA) is present nearer to the start codon.
	Shows the genomic organization of GDF15 gene.
Transcription	The expression of GDF15/MIC-1 is upregulated by IL1β, TNFa, IL2, MCSF, TGFβ and p53. Androgen also regulates the expression of GDF15/MIC-1 in vitro and in vivo. In prostate cancer cells, calcitriol induces GDF15/MIC-1 expression. Furthermore, it has been shown that the basal transcription of MIC-1 gene is regulated by Sp1 and Sp3.

	Shows the structural organization and processing of GDF15 protein. RXXR-motif for cleavage; N, amino-terminal region; C, cysteine.
Description	The premature GDF/PDF/MIC-1 protein consists of 308 amino acids that contain a 29 amino acid signal peptide, a 167 amino acid propeptide, and a 112 amino acid mature protein. The mature protein is secreted as a homodimer linked by disulfide bonds and is released from the propeptide following intracellular cleavage at RXXR furine-like cleavage site. The mature peptide of GDF-1/MIC-1 contains two additional cysteine residues in addition to the seven conserved cysteines necessary for the cysteine knot, a structural hallmark of this TGF-β superfamily. The exact function of these two additional cysteine residues is still unknown. The propeptide has a consensus N-linked glycosylation site in it. Unlike all other TGF-β superfamily members, MIC-1 mature peptide can be correctly folded and secreted without a propeptide. The propeptide plays a novel role in proteosomal targeting of the monomeric precursor and ensures that only dimeric precursor exists in the endoplasmic reticulum.
Expression	GDF15/PDF/MIC-1 is expressed at high levels in placenta, adult prostate, skin and at a low level in several other tissues including colon, kidney and fetal brain.
Localisation	MIC-1 is an extracelluarly localized secretory protein.
Function	GDF15/MIC-1 plays diverse biological functions in varied cellular context. It has been proposed that GDF15/MIC-1 can regulate the late phase macrophage activation by inhibiting TNF-a as an autocrine/paracrine regulatory molecule. Its role in the early stages of endochondrial bone formation, hematopoietic development, embryonic implantation and placental function has been reported. Animal studies have shown the role of GDF15/MIC-1 as a central regulator of appetite and body weight. For midbrain dopaminergic neurons, GDF15/MIC-1 acts as a both neurotrophic and neuroprotective factor, in vitro and in vivo. A role of GDF15/MIC-1 in cancer progression has also been reported by impacting on cell signaling.
Homology	It shares a significant homology with the GDF15 gene of Pan troglodytes, Bos Taurus and Canis lupus familiaris. In addition, it is also similar to Gdf15 gene of Mus musculus and Rattus norvegicus.

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