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GDF15 (growth differentiation factor 15)

Identity

Other namesMIC-1 (macrophage inhibitory cytokine-1)
NAG-1
NRG-1
PDF (prostate derived factor)
PLAB
PTGF-β
PTGFB
HGNC (Hugo) GDF15
LocusID (NCBI) 9518
Location 19p13.11
Location_base_pair Starts at 18496968 and ends at 18499986 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

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.

Protein

 
  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.

Implicated in

Entity Various Cancers
Disease 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.
Prognosis 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.
Oncogenesis 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 Thalassemia
Disease Expanded erythroid compartment secrete high level of GDF15, which leads to iron overload in thalassemia syndromes by inhibiting hepcidin expression.
  

External links

Nomenclature
HGNC (Hugo)GDF15   30142
Cards
AtlasGDF15ID40701ch19p13
Entrez_Gene (NCBI)GDF15  9518  growth differentiation factor 15
GeneCards (Weizmann)GDF15
Ensembl (Hinxton)ENSG00000130513 [Gene_View]  chr19:18496968-18499986 [Contig_View]  GDF15 [Vega]
AceView (NCBI)GDF15
Genatlas (Paris)GDF15
WikiGenes9518
SOURCE (Princeton)NM_004864
Genomic and cartography
GoldenPath (UCSC)GDF15  -  19p13.11   chr19:18496968-18499986 +  19p13.11   [Description]    (hg19-Feb_2009)
EnsemblGDF15 - 19p13.11 [CytoView]
Mapping of homologs : NCBIGDF15 [Mapview]
OMIM605312   
Gene and transcription
Genbank (Entrez)AB000584 AF003934 AF019770 AF173860 AK225431
RefSeq transcript (Entrez)NM_004864
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NT_011295 NW_001838484 NW_001841750 NW_004929414
Consensus coding sequences : CCDS (NCBI)GDF15
Cluster EST : UnigeneHs.616962 [ NCBI ]
CGAP (NCI)Hs.616962
Alternative Splicing : Fast-db (Paris)GSHG0014711
Alternative Splicing GalleryENSG00000130513
Gene ExpressionGDF15 [ NCBI-GEO ]     GDF15 [ SEEK ]   GDF15 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ99988 (Uniprot)
NextProtQ99988  [Medical]
With graphics : InterProQ99988
Splice isoforms : SwissVarQ99988 (Swissvar)
Domaine pattern : Prosite (Expaxy)TGF_BETA_1 (PS00250)    TGF_BETA_2 (PS51362)   
Domains : Interpro (EBI)TGF-b_C    TGF-beta-rel   
Related proteins : CluSTrQ99988
Domain families : Pfam (Sanger)TGF_beta (PF00019)   
Domain families : Pfam (NCBI)pfam00019   
Domain families : Smart (EMBL)TGFB (SM00204)  
DMDM Disease mutations9518
Blocks (Seattle)Q99988
Human Protein AtlasENSG00000130513
Peptide AtlasQ99988
HPRD05608
IPIIPI00306543   
Protein Interaction databases
DIP (DOE-UCLA)Q99988
IntAct (EBI)Q99988
FunCoupENSG00000130513
BioGRIDGDF15
InParanoidQ99988
Interologous Interaction database Q99988
IntegromeDBGDF15
STRING (EMBL)GDF15
Ontologies - Pathways
Ontology : AmiGOcytokine activity  extracellular region  extracellular space  signal transduction  transforming growth factor beta receptor signaling pathway  cell-cell signaling  growth factor activity  
Ontology : EGO-EBIcytokine activity  extracellular region  extracellular space  signal transduction  transforming growth factor beta receptor signaling pathway  cell-cell signaling  growth factor activity  
REACTOMEGDF15
Protein Interaction DatabaseGDF15
Wikipedia pathwaysGDF15
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)GDF15
SNP (GeneSNP Utah)GDF15
SNP : HGBaseGDF15
Genetic variants : HAPMAPGDF15
1000_GenomesGDF15 
ICGC programENSG00000130513 
Somatic Mutations in Cancer : COSMICGDF15 
CONAN: Copy Number AnalysisGDF15 
Mutations and Diseases : HGMDGDF15
OMIM605312   
GENETestsGDF15
Disease Genetic AssociationGDF15
Huge Navigator GDF15 [HugePedia]  GDF15 [HugeCancerGEM]
Genomic VariantsGDF15  GDF15 [DGVbeta]
Exome VariantGDF15
dbVarGDF15
ClinVarGDF15
snp3D : Map Gene to Disease9518
General knowledge
Homologs : HomoloGeneGDF15
Homology/Alignments : Family Browser (UCSC)GDF15
Phylogenetic Trees/Animal Genes : TreeFamGDF15
Chemical/Protein Interactions : CTD9518
Chemical/Pharm GKB GenePA134866647
Clinical trialGDF15
Cancer Resource (Charite)ENSG00000130513
Other databases
Probes
Litterature
PubMed157 Pubmed reference(s) in Entrez
CoreMineGDF15
iHOPGDF15

Bibliography

MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily.
Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbin JM, Breit SN.
Proc Natl Acad Sci USA. 1997 Oct 14; 94(21): 11514-9.
PMID 9326641
 
Cloning and characterization of a novel member of the transforming growth factor beta/bone morphogenic protein family.
Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA, Thompson DD.
J Biol Chem. 1998 May 29; 273(22): 13760-7.
PMID 9593718
 
Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1).
Bottner M, Laaff M, Schechinger B, Rappold G, Unsicker K, Suter-Crazzolara C.
Gene. 1999 Sep 3; 237(1): 105-11.
PMID 10524241
 
The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1.
Bauskin AR, Zhang HP, Fairlie WD, He XY, Russell PK, Moore AG, Brown DA, Stanley KK, Breit SN.
EMBO J. 2000 May 15; 19(10): 2212-20.
PMID 10811612
 
The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women.
Moore AG, Brown DA, Fairlie WD, Bauskin AR, Brown PK, Munier ML, Russell PK, Salamonsen LA, Wallace EM, Breit SN.
J Clin Endocrinol Metab. 2000 Dec; 85(12): 4781-8.
PMID 11134143
 
Molecular cloning and characterization of human nonsteroidal anti-inflammatory drug-activated gene promoter. Basal transcription is mediated by Sp1 and Sp3.
Baek SJ, Horowitz JM, Eling TE.
J Biol Chem. 2001 Sep 7; 276(36): 33384-92.
PMID 11445565
 
Anoxia induces macrophage inhibitory cytokine-1 (MIC-1) in glioblastoma cells independently of p53 and HIF-1.
Albertoni M, shaw PH, Nozaki M, Godard S, Tenan M, Hamou MF, Fairlie DW, Breit SN, Paralkar VM, de Tribolet N, Van Meir EG, Hegi ME.
Oncogene. 2002 Jun 20; 21(27): 4212-9.
PMID 12082608
 
Autocrine 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, Lin D, Sun Y, Lee KO, Lobie PE.
J Biol Chem. 2002 Jul 19; 277(29): 26662-72.
PMID 11994274
 
Expression profile of differentially-regulated genes during progression of androgen-independent growth in human prostrate cancer cells.
Karan D, Kelly DL, Rizzino A, Lin MF, Batra SK.
Carcinogenesis. 2002 Jun; 23(6): 967-75.
PMID 12082018
 
Dysregulated expression of MIC-1/PDF in human prostrate tumor cells.
Karan D, Chen SJ, Johansson SL, Singh AP, Paralkar VM, Lin MF, Batra SK.
Biochem Biophys Res Commun. 2003 Jun 6; 305(3): 598-604.
PMID 12763036
 
Macrophage inhibitory cytokine-1 induces the invasiveness of gastric cancer cells by up-regulating the urokinase-type plasminogen activator system.
Lee DH, Yang Y, Lee SJ, Kim KY, Koo TH, Shin SM, Song KS, Lee YH, Kim YJ, Lee JJ, Choi I, Lee JH.
Cancer Res. 2003 Aug 1; 63 (15): 4648-55.
PMID 12907645
 
Role of macrophage inhibitory cytokine-1 in tumorigenesis and diagnosis of cancer.
Bauskin AR, Brown DA, Kuffner T, Johnen H, Luo XW, Hunter M, Breit SN.
Cancer Res. 2006 May 15; 66(10): 4983-6.
PMID 16707416
 
Prostate-derived factor as a paracrine and autocrine factor for the proliferation of androgenreceptor-positive human prostate cancer cells.
Chen SJ, Karan D, Johansson SL, Lin FF, Zeckser J, Singh AP, Batra SK, Lin MF.
Prostate. 2007 Apr 1; 67(5): 557-71
PMID 17221842
 
High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin.
Tanno T, Bhanu NV, Oneal PA, Goh SH, Staker P, Lee YT, Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs R, Ganz T, Leitman SF, Fucharoen S, Miller JL.
Nat Med. Sep; 13(9): 1096-101.
PMID 17721544
 
Molecular alterations in prostrate carcinomas that associate with in vivo exposure to chemotherapy identification of a cytoprotective mechanism involving growth differentiation factor 15.
Huang CY, Beer TM, Higano CS, True LD, Vessella R, Lange PH, Garzotto M, Nelson PS.
Clin Cancer Res. 2007 Oct 1; 13(19): 5825-33.
PMID 17908975
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written04-2008Shantibhusan Senapati, Ajay P Singh, Surinder K Batra
Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Durham Research center 7005, Omaha, NE 68198-5870, USA

Citation

This paper should be referenced as such :
Senapati S, Singh AP, Batra SK . GDF15 (growth differentiation factor 15). Atlas Genet Cytogenet Oncol Haematol. April 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/GDF15ID40701ch19p13.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44426/1/04-2008-GDF15ID40701ch19p13.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:34:36 CEST 2014

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