GDF15

Official Full Name

growth differentiation factor 15

Organism

Homo sapiens

GeneID

9518

Background

This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. The protein is expressed in a broad range of cell types, acts as a pleiotropic cytokine and is involved in the stress response program of cells after cellular injury. Increased protein levels are associated with disease states such as tissue hypoxia, inflammation, acute injury and oxidative stress. [provided by RefSeq, Aug 2016]

Synonyms

HG; PDF; MIC1; PLAB; MIC-1; NAG-1; PTGFB; GDF-15;

Bio Chemical Class

Growth factor

Protein Sequence

MPGQELRTVNGSQMLLVLLVLSWLPHGGALSLAEASRASFPGPSELHSEDSRFRELRKRYEDLLTRLRANQSWEDSNTDLVPAPAVRILTPEVRLGSGGHLHLRISRAALPEGLPEASRLHRALFRLSPTASRSWDVTRPLRRQLSLARPQAPALHLRLSPPPSQSDQLLAESSSARPQLELHLRPQAARGRRRARARNGDHCPLGPGRCCRLHTVRASLEDLGWADWVLSPREVQVTMCIGACPSQFRAANMHAQIKTSLHRLKPDTVPAPCCVPASYNPMVLIQKTDTGVSLQTYDDLLAKDCHCI

Open

Disease

Cachexia, Heart failure, Obesity

Approved Drug

Clinical Trial Drug

3 +

Discontinued Drug

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Detailed Information

Growth and differentiation factor 15 (GDF15), formerly known as NSAID-activated gene 1 (NAG-1) and macrophage inhibitory cytokine 1 (MIC-1), is a divergent transforming growth factor β (TGF-β) family member historically associated with cardiovascular disease, cancer cachexia, and a range of other diseases with inflammatory etiologies. In the past decade, evidence has emerged in genetic knockout systems that GDF15 may be involved in body weight regulation and metabolic health. GDF15 administration lowers body weight, largely by reducing appetite. Some studies have also shown that GDF15 can directly increase thermogenesis and improve insulin sensitivity. Recently, the GDNF family receptor α-like (GFRAL), located in the area postrema of the hindbrain, was identified as the receptor mediating the anorexic effects of GDF15.

GDF15 Function in Normal Physiology and Disease

In normal physiology, GDF15 is highly expressed in the placenta and the prostate, for which it was also called placental transformation growth factor-β (PTGFB) in some literature. GDF15 is also expressed at lower levels in epithelial cells of the mammary glands, liver, lung, kidney, pancreas, colon, and gastrointestinal tract. Expression of GDF15 has also been reported in the human central and peripheral nervous system. The physiological serum concentration of GDF15 is about 450 pg/ml in humans and about 100 pg/ml in mice. When studying malignant diseases, GDF15 serum concentration has been found to increase to 10,000-100,000 pg/ml in humans and roughly 5000 pg/ml in mice. This increase in GDF15 serum level has been suggested as a potential biomarker of cancer progression. Circulating concentrations of GDF15 are also increased in many other pathological conditions in addition to cancer including metabolic diseases, inflammation and cardiovascular diseases such as heart failure and hypertrophy.

GDF15 is upregulated in response to a variety of stimuli including oxidized low-density lipoprotein (oxLDL), cytokines and growth factors such as TNF-α, interleukin-1β (IL-1β), angiotensin II, TGFβ, and macrophage colony-stimulating factor (M-CSF). GDF15 seems to be an anti-inflammatory factor that may act by inhibiting macrophage activation. GDF15 also inhibits a variety of cytokines, including interleukin-6 (IL-6), interferon gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor alpha (TNF-α); it also inhibits endotoxin-induced sepsis induced by LPS following acute kidney injury (AKI) and myocardial dysfunction. Therefore, GDF15 plays a protective role in LPS-induced septic AKI and myocardial dysfunction through anti-inflammatory activity.

GDF15 and Cancer

Similar to other TGFβ members, GDF15 seems to play multiple roles in cancer. In the early stages of malignancy, GDF15 might play an anti-cancer role, whereas in the advanced stages of cancer, it may play a role of tumor promoting factor. This difference may be due to the tumor suppressor activity of GDF15 in early stages of tumor development and progression and then becoming a tumor promoter as the tumor progresses into a malignant tumor. Other members of TGFβ superfamily have also demonstrated similar pro and anti-tumor effects depending on tumor origin, stage of the tumor and the cellular context such as transcriptional regulators and epigenetic status.

An in vitro study led to speculation that GDF15 is upregulated through p53 protein recruitment and plays an apoptotic role in inhibiting bladder carcinoma cell growth and proliferation. This apoptotic function of GDF15 against tumorigenesis is consistent with some other cancer studies on head, neck, and breast cancers. In contrast, it has been reported GDF15 upregulates CyclinD1 and CyclinE1 and downregulates p21 via activation of both PI3K/AKT and MAPK/ERK signalling pathways, leading to cervical cancer cell proliferation. A tumor microenvironment study of osteocytes in prostate cancer bone metastasis showed that increased GDF15 production by osteocytes may promote tumorigenesis through crosstalk activation of early growth response protein 1 (EGR1), which then stimulates the prostate cancer cells in a positive feedback loop, increasing cancer cell proliferation. Since GFRAL is expressed in prostate cancer cells, it seems likely that GDF15 mediates its pro-metastatic activity in prostate cancer through the GFRAL receptor.

References:

Assadi A, et al. GDF15, an update of the physiological and pathological roles it plays: a review. Pflügers Archiv-European Journal of Physiology, 2020: 1-12.
Kleinert M, et al. Exercise increases circulating GDF15 in humans. Molecular metabolism, 2018, 9: 187-191.
Luan H H, et al. GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell, 2019, 178(5): 1231-1244. e11.
Emmerson P J, et al. GDF15 and growth control. Frontiers in physiology, 2018, 9: 1712.

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