Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1)

Böttner, Martina; Laaff, Martin; Schechinger, Birgit; Rappold, Gudrun; Unsicker, Klaus; Suter‐Crazzolara, Clemens

doi:10.1016/s0378-1119(99)00309-1

Cited by 127 publications

(106 citation statements)

References 20 publications

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“…Expression of Recombinant Human GDF-15-Full-length GDF-15 cDNA was cloned and sequenced as described previously (13). Recombinant human GDF-15 protein was expressed in baculovirus-infected insect SF9 cells and purified from supernatants as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

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Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways

Subramaniam¹,

Strelau²,

Unsicker

2003

Journal of Biological Chemistry

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116

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Growth differentiation factor-15 (GDF-15) is a novel member of the transforming growth factor-␤ superfamily and has been shown to be induced in neurons subsequent to lesions. We have therefore begun to study its putative role in the regulation of neuron survival and apoptosis. Cultured cerebellar granule neurons (CGN) survive when maintained in high K ؉ (25 mM) but undergo apoptosis when switched to low K ؉ (5 mM). GDF-15 prevented death of CGN in low K ؉ . This effect could be blocked by phosphatidylinositol 3-kinase/Akt pathway inhibitors LY294002 or wortmannin. In contrast, mitogen-activated protein kinase (MEK)/extracellular-signal-regulated kinase (ERK) pathway inhibitors U0126 and PD98059 potentiated GDF-15 mediated survival and prevented cell death in low K ؉ even without factor treatment. Immunoblots revealed GDF-15-induced phosphorylation of Akt and glycogen synthase kinase-3␤. This activation was suppressed by phosphatidylinositol 3-kinase inhibitors. Low K ؉ induced delayed and persistent ERK activation, which was blocked by MEK inhibitors or GDF-15. ERK activation induced c-Jun, a member of the AP-1 transcription factor family. GDF-15 or U0126 prevented c-Jun activation. Furthermore, we show that GDF-15 prevented generation of reactive oxygen species, a known activator of ERK. Together, our data suggest that GDF-15 prevents apoptosis in CGN by activating Akt and inhibiting endogenously active ERK. Transforming growth factor-␤s (TGF-␤s)1 comprise a superfamily of contextually acting cytokines with a broad array of biological activities. Depending on the developmental stage and cell type TGF-␤s regulate diverse processes including development, cell proliferation, differentiation, survival, and death (1-4). Members of the TGF-␤ superfamily can be subdivided into subfamilies of structurally closer related proteins, including the TGF-␤s 1-3, bone morphogenetic proteins, the growth/differentiation factors (GDFs), activins, and the glial cell line-derived neurotrophic factor (GDNF) family (5-7).All TGF-␤ famliy members, except members of the GDNF subfamily, signal through heteromeric complexes of type I and type II serine/threonine kinases receptors. Within the type I and type II receptor families there are several subgroups, e.g. bone morphogenetic protein receptors, depending on their respective ligands (for reviews, see Refs. 7 and 8). GDNF, neurturin, persephin, and artemin signal through a heteromeric receptor complex consisting of the receptor tyrosine kinase Ret (9, 10) and glycosylphosphatidylinositol-linked ␣-receptors (11).We and others (12, 13) have recently cloned a novel member of the TGF-␤ superfamily, GDF-15/macrophage inhibitory cytokine-1 (MIC-1). The protein does not belong to one of the known TGF-␤ subfamilies and represents a divergent member of the TGF-␤ superfamily. GDF-15 is widely synthesized in the central nervous system, most strongly expressed in the choroid plexus, and secreted into the cerebrospinal fluid, from where it may penetrate into the brain parenchyma (14 -16). We have p...

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Section: Methodsmentioning

confidence: 99%

“…We and others (12,13) have recently cloned a novel member of the TGF-␤ superfamily, GDF-15/macrophage inhibitory cytokine-1 (MIC-1). The protein does not belong to one of the known TGF-␤ subfamilies and represents a divergent member of the TGF-␤ superfamily.…”

mentioning

confidence: 99%

Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways

Subramaniam¹,

Strelau²,

Unsicker

2003

Journal of Biological Chemistry

Self Cite

116

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“…Its DNA sequence is 2746 bp long and consists of two exons separated by a single intron. 9 There are at least two GDF-15 alleles, which were identified and characterized in detail by Breit's group. 10 The polymorphism, labeled H6D, consists of a single C-G transversion in exon II at 2423 bp, resulting in a switch from histidine to aspartic acid at codon 202 of the mature protein.…”

Section: Gdf-15 Sequence and Structurementioning

confidence: 99%

“…The GDF-15 promoter sequence is conserved in murine, rat and human tissues and consists of a TATA-like sequence as well as SP1 and AP1/2 consensus sites. 9 The promoter of GDF-15 contains two distinct p53-binding sites with different binding affinity to p53 in vitro. Interestingly, Wong et al 51 identified a novel p53 transcriptional repressor element in close proximity of the p53-binding sites, suggesting a complex regulation of activation of GDF-15 in a manner dependent on cell or signaling context.…”

Section: Regulation Of Gdf-15 Expressionmentioning

confidence: 99%

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

Vaňhara

Hampl

Kozubı́k

et al. 2012

Prostate Cancer Prostatic Dis

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Deregulation of expression and function of cytokines belonging to the transforming growth factor-b (TGF-b) family is often associated with various pathologies. For example, this cytokine family has been considered a promising target for cancer therapy. However, the detailed functions of several cytokines from the TGF-b family that could have a role in cancer progression and therapy remain unclear. One of these molecules is growth/differentiation factor-15 (GDF-15), a divergent member of the TGF-b family. This stress-induced cytokine has been proposed to possess immunomodulatory functions and its high expression is often associated with cancer progression, including prostate cancer (PCa). However, studies clearly demonstrating the mechanisms for signal transduction and functions in cell interaction, cancer progression and therapy are still lacking. New GDF-15 roles have recently been identified for modulating osteoclast differentiation and for therapy for PCa bone metastases. Moreover, GDF-15 is as an abundant cytokine in seminal plasma with immunosuppressive properties. We discuss studies that focus on the regulation of GDF-15 expression and its role in tissue homeostasis, repair and the immune response with an emphasis on the role in PCa development.

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“…[4][5][6][7] GDF15 is expressed in several organs, including liver, lung, kidney, and exocrine glands. 8,9 In mice, GDF15 acts as a cardioprotective factor released by the myocardium, and as a neurotrophic factor for midbrain dopaminergic neurons. [10][11][12] Mice treated with systemic GDF15 and transgenic mice overexpressing GDF15 show hypophagia and reduced body weight.…”

Section: Introductionmentioning

confidence: 99%

The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice

et al. 2012

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Characterization of the rat, mouse, and human genes of growth/differentiation factor-15/macrophage inhibiting cytokine-1 (GDF-15/MIC-1)

Cited by 127 publications

References 20 publications

Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways

Growth Differentiation Factor-15 Prevents Low Potassium-induced Cell Death of Cerebellar Granule Neurons by Differential Regulation of Akt and ERK Pathways

Growth/differentiation factor-15: prostate cancer suppressor or promoter?

The murine growth differentiation factor 15 is not essential for systemic iron homeostasis in phlebotomized mice

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