Download Gene Section GDF15 (growth differentiation factor 15) Atlas of Genetics and Cytogenetics

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GDF15 (growth differentiation factor 15)
Shantibhusan 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 (SS, APS, SKB)
Published in Atlas Database: April 2008
Online updated version: http://AtlasGeneticsOncology.org/Genes/GDF15ID40701ch19p13.html
DOI: 10.4267/2042/44426
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Identity
Protein
Other names: MIC-1 (macrophage inhibitory
cytokine-1); NAG-1; NRG-1; PDF (prostate derived
factor); PLAB; PTGF-β; PTGFB
HGNC (Hugo): GDF15
Location: 19p13.11
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.
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.
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 genomic organization of GDF15 gene.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(3)
204
GDF15 (growth differentiation factor 15)
Senapati S, et al.
Shows the structural organization and processing of GDF15 protein. RXXR-motif for cleavage; N, amino-terminal region; C, cysteine.
Expression
Implicated in
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.
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 Uroki-nase-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
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 implanta-tion
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.
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(3)
205
GDF15 (growth differentiation factor 15)
Senapati S, et al.
role of GDF15/MIC-1 in the induction of apoptosis via
both p53-dependent and independent mechanisms.
1 (MIC-1) in glioblastoma cells independently of p53 and HIF1. Oncogene. 2002 Jun 20;21(27):4212-9
Thalassemia
Graichen R, Liu D, Sun Y, Lee KO, Lobie PE. Autocrine human
growth hormone inhibits placental transforming growth factorbeta gene transcription to prevent apoptosis and allow cell
cycle progression of human mammary carcinoma cells. J Biol
Chem. 2002 Jul 19;277(29):26662-72
Disease
Expanded erythroid compartment secrete high level of
GDF15, which leads to iron overload in thala-ssemia
syndromes by inhibiting hepcidin expression.
Karan D, Kelly DL, Rizzino A, Lin MF, Batra SK. Expression
profile of differentially-regulated genes during progression of
androgen-independent growth in human prostate cancer cells.
Carcinogenesis. 2002 Jun;23(6):967-75
References
Karan D, Chen SJ, Johansson SL, Singh AP, Paralkar VM, Lin
MF, Batra SK. Dysregulated expression of MIC-1/PDF in
human prostate tumor cells. Biochem Biophys Res Commun.
2003 Jun 6;305(3):598-604
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M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh
BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN.
MIC-1, a novel macrophage inhibitory cytokine, is a divergent
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cytokine-1 induces the invasiveness of gastric cancer cells by
up-regulating the urokinase-type plasminogen activator
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characterization of a novel member of the transforming growth
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and autocrine factor for the proliferation of androgen receptorpositive human prostate cancer cells. Prostate. 2007 Apr
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AG, Brown DA, Stanley KK, Breit SN. The propeptide of
macrophage inhibitory cytokine (MIC-1), a TGF-beta
superfamily member, acts as a quality control determinant for
correctly folded MIC-1. EMBO J. 2000 May 15;19(10):2212-20
Huang CY, Beer TM, Higano CS, True LD, Vessella R, Lange
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carcinomas that associate with in vivo exposure to
chemotherapy: identification of a cytoprotective mechanism
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Moroney JW, Reed CH, Luban NL, Wang RH, Eling TE, Childs
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GDF15 in thalassemia suppress expression of the iron
regulatory protein hepcidin. Nat Med. 2007 Sep;13(9):1096101
Baek SJ, Horowitz JM, Eling TE. Molecular cloning and
characterization of human nonsteroidal anti-inflammatory drugactivated gene promoter. Basal transcription is mediated by
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This article should be referenced as such:
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. Anoxia induces macrophage inhibitory cytokine-
Atlas Genet Cytogenet Oncol Haematol. 2009; 13(3)
Senapati S, Singh AP, Batra SK. GDF15 (growth differentiation
factor 15). Atlas Genet Cytogenet Oncol Haematol. 2009;
13(3):204-206.
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