GDF15 (growth differentiation factor 15)

2008-04-01   Shantibhusan Senapati , Ajay P Singh , Surinder K Batra 

Department of Biochemistry, Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Durham Research center 7005, Omaha, NE 68198-5870, USA





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.
Atlas Image
Shows the genomic organization of GDF15 gene.


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.


Atlas Image
Shows the structural organization and processing of GDF15 protein. RXXR-motif for cleavage; N, amino-terminal region; C, cysteine.


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.


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.


MIC-1 is an extracelluarly localized secretory protein.


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.


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.

Implicated in

Entity name
Various Cancers
GDF15/MIC-1 over expression is associated with different cancers, including gastric, pancreatic, prostate and colorectal cancer. It has been shown that measurement of serum GDF15/MIC-1 level aids in the diagnosis of prostrate and pancreatic cancer.
Recently, a direct association of elevated serum GDF15/MIC-1 and metastatic prostrate, colorectal, and breast cancer has been reported. Additionally, higher serum GDF15/MIC-1 level was correlated with higher incidence of lymph node metastasis and shorter relapse and shorter overall survival period.
The oncogenic property of GDF15/MIC-1 in different cancer has been reported. In prostrate cancer, it promotes AR-positive prostrate cancer cell proliferation trough the activation of ERK1 / ERK2 signal pathway. Additionally, GDF15 promotes the drug resistance property of prostrate cancer cells. The role of GDF15/MIC-1 in promoting the invasive property of gastric cancer cells has been reported. This may be due to GDF15/MIC-1 mediated up-regulation of Urokinase-type plasminogen activator system. In contrast, some studies have reported an antitumorigenic role of GDF15/MIC-1 in colon, breast and glioblastoma cell lines. Most of these reports suggest a role of GDF15/MIC-1 in the induction of apoptosis via both p53-dependent and independent mechanisms.
Entity name
Expanded erythroid compartment secrete high level of GDF15, which leads to iron overload in thalassemia syndromes by inhibiting hepcidin expression.


Pubmed IDLast YearTitleAuthors
120826082002Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1.Albertoni M et al
114455652001Molecular cloning and characterization of human nonsteroidal anti-inflammatory drug-activated gene promoter. Basal transcription is mediated by Sp1 and Sp3.Baek SJ et al
167074162006Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer.Bauskin AR et al
93266411997MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.Bootcov MR et al
105242411999Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1).Böttner M et al
172218422007Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgen receptor-positive human prostate cancer cells.Chen SJ et al
119942742002Autocrine human growth hormone inhibits placental transforming growth factor-beta gene transcription to prevent apoptosis and allow cell cycle progression of human mammary carcinoma cells.Graichen R et al
179089752007Molecular alterations in prostate carcinomas that associate with in vivo exposure to chemotherapy: identification of a cytoprotective mechanism involving growth differentiation factor 15.Huang CY et al
127630362003Dysregulated expression of MIC-1/PDF in human prostate tumor cells.Karan D et al
120820182002Expression profile of differentially-regulated genes during progression of androgen-independent growth in human prostate cancer cells.Karan D et al
129076452003Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system.Lee DH et al
111341432000The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women.Moore AG et al
95937181998Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family.Paralkar VM et al
177215442007High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.Tanno T et al

Other Information

Locus ID:

NCBI: 9518
MIM: 605312
HGNC: 30142
Ensembl: ENSG00000130513


dbSNP: 9518
ClinVar: 9518
TCGA: ENSG00000130513


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
93266411997MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.261
177215442007High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.229
163971412006The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury.148
179824622007Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1.127
126241832003Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum.113
112596362001Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities.104
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
150731152004Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.80
150731152004Serum macrophage inhibitory cytokine 1 as a marker of pancreatic and other periampullary cancers.80
128556422003MIC-1 serum level and genotype: associations with progress and prognosis of colorectal carcinoma.78


Shantibhusan Senapati ; Ajay P Singh ; Surinder K Batra

GDF15 (growth differentiation factor 15)

Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

Online version: