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FLASH GENE
Symbol GDF15 contributors: mct/npt - updated : 08-06-2015
HGNC name growth differentiation factor 15
HGNC id 30142
Location 19p13.11      Physical location : 18.496.967 - 18.499.986
Synonym name
  • PTGF-beta
  • prostate-derived factor
  • NSAID (nonsteroidal anti-inflammatory drug)-activated protein 1
  • macrophage inhibitory cytokine 1
  • placental bone morphogenetic protein
  • Synonym symbol(s) PDF, MIC1, PLAB, MIC-1, NAG-1, PTGFB, C4E3
    DNA
    TYPE functioning gene
    STRUCTURE 3.02 kb     2 Exon(s)    1 Copie(s)
    regulatory sequence Promoter (TATA box)
    text structure
  • TP63-binding site within the GDF15 promoter region required for the TP63-mediated transcriptional activation of GDF15, and TP63 was recruited onto this site (Ishikawa 2008)
  • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 1220 - 308 - 1998 9593718
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinelarge intestinecolon highly
    Reproductivefemale systemplacenta  highly
     male systemprostate  highly Homo sapiens
    Skin/Tegumentskin   highly
    Urinarykidney   lowly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectiveadipose  highly
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Blood/Hematopoieticerythroid Homo sapiens
    Lymphoid/Immunemacrophage
    not specificadipocyte
    Skin/Tegumentkeratinocyte
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, pregnancy
    Text skin and cartilagenous tissue of the developing embryo, highly in placenta
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a hydrophobic signal sequence
  • a seven-cysteine domain
  • a potential N-linked glycosylation site
  • mono polymer homomer , dimer
    isoforms Precursor synthesized as a 40-kDa propeptide that is cleaved to release a 25-kDa mature protein into the circulation
    HOMOLOGY
    interspecies ortholog to murine Gdf15
    ortholog to rattus gdf15
    Homologene
    FAMILY
  • TGF-beta/BMP family, bone morphogenic family of proteins
  • CATEGORY regulatory , secretory , signaling growth factor
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm
    intracellular,nucleus
    text
  • secreted
  • expressed in not only the cytoplasm and ECM, but also in the nucleus
  • basic FUNCTION
  • regulates tissue differenciation and maintenance
  • reduces the growth of granulocytes and macrophages, as an autocrine/paracrine regulatory molecule
  • may promote fetal survival by suppressing the production of maternally derived proinflammatory cytokines within the uterus
  • activates signal transduction
  • regulator of hepcidin, not the sole regulator of its expression, but instead contributes to the suppression of hepcidin in the pathological setting of thalassemia
  • antihypertrophic factor which is induced in the heart in response to pressure overload and plays an important
  • seems to be an important determinant of renal collecting duct lengthening (
  • regulatory role in the process of hypertrophy (Wang 2009)
  • involved in the control of multiple cellular processes and mediates cachexia through the inhibition of appetite (Ding 2009)
  • may have a paracrine role in the modulation of adipose tissue function and body fat mass (Ding 2009)
  • production of GDF15 by erythroid cells is dependent on both EPO and TFR2
  • is among the erythroid factors down-regulating hepcidin and contributing to iron overload in conditions of dyserythropoiesis
  • could play a pivotal role in the pathogenesis of bone loss relevant to hypoxia through promotion of osteoclastogenesis after secretion from adjacent osteocytes during disuse and/or ischemia in bone
  • specifically inhibits platelet integrin activation
  • play a role in cell proliferation, apoptosis, cell metastasis, and angiogenesis through autocrine and paracrine signaling
  • may be one of the critical molecules that inhibit dendritic cells maturation and function and are involved in tumor immune escape
  • regulates likely migration and proliferation by promoting EGFR signalling in the postnatal hippocampus (HP)
  • nuclear GDF15 contributes to inhibition of the Smad pathway by interrupting the Smad complex, and controls transcriptional regulation in the Smad pathway
  • secreted cytokine, a direct target of TP53, playing a role in cell proliferation and apoptosis
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • targeted by the tumor suppressor TP53 (its expression is increased by stress conditions such as anoxia, cancer and tissue injury)
  • TWSG1 interferes with BMP-mediated hepcidin expression and may act with GDF15 to dysregulate iron homeostasis in thalassemia syndromes
  • GDF15 can be regulated through RBM38 via mRNA stability
  • CALU-15 has a critical role in promoting filopodia formation and cell migration by upregulating the GDF15 transcription
  • novel regulation of KCNB1 by GDF15 mediated through the TGFBR2-activated AKT1/MTOR pathway, which is a previously uncharacterized SMAD-independent mechanism of GDF15 signalling
  • has a pro-survival and anti-oxidant role in hyperoxia and TP53 plays a key role in its induction
  • C2CD5 silencing attenuates TGFB1/SMAD signaling activation at least in part through the downregulation of GDF15
  • cell & other
    REGULATION
    induced by RA/PMA, in a dependent manner of the level of differentiation of the cell, with increased responsiveness corresponding to the degree of differenciation
    Other up-regulated by IL1 beta, TNF alpha, IL2, MCSF, TGF beta
    cleaved by MMP14 (contributes to tumor cell proliferation through the cleavage of GDF15, which down-regulates cell proliferation by inducing activation of TP53 and CDKN1A synthesis)(ElAziz 2007)
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional     --over  
    arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression
    tumoral     --over  
    in prostate cancer (should be evaluated as a potential diagnostic and prognostic biomarker)
    tumoral     --low  
    in primary glioblastoma (Strelau 2008)
    constitutional     --low  
    is associated with atrophic inflammatory lesions of the prostate
    tumoral     --over  
    increased significantly in patients with the severe cancer-related anemia (CRA), and elevation of GDF15 concentrations suppressed hepcidin expression
    constitutional     --over  
    prominently upregulated in the retina after optic nerve crush but does not directly interfere with the magnitude and temporal progression of retinal ganglion cell (RGC) death
    Susceptibility to left ventricular remodelling in essential hypertension
    Variant & Polymorphism SNP
  • causing a his6-to-asp substitution in the GDF15 protein, that could alter its function
  • promoter haplotype -3148G variant increases GDF15 transcription activity and is associated with favourable left ventricular remodelling in essential hypertension (Wang 2009)
  • Candidate gene GDF15 expression might be exploited as a useful indicator for distinguishing primary from other glial derived tumors (Strelau 2008)
    Marker
  • plasma GDF15 levels is associated with chronic heart failure (CHF) in coronary atherosclerosis patients and can be used as biomarker
  • Therapy target
    SystemTypeDisorderPubmed
    bloodhemoglobin 
    potential therapeutic target for -thalassemia syndromes
    cancer  
    may be a novel target in tumor immunotherapy
    ANIMAL & CELL MODELS
  • Gdf-15-deficient mice exhibit progressive postnatal motor and sensory neuron losses implying essential functions of Gdf-15 in neuronal survival