MIC-1 is a novel TGF-β superfamily cytokine associated with macrophage activation

Fairlie, W. Douglas; Moore, Anthony G.; Bauskin, Asne R.; Russell, Patricia K; Zhang, H P; Breit, Samuel N.

doi:10.1002/jlb.65.1.2

Cited by 231 publications

(186 citation statements)

References 9 publications

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“…Screening of Atlas Human Cancer cDNA expression array using RNA from pcDNA3 and CA-AKT cells revealed up-regulation of macrophage inhibitory cytokine (MIC-1) by AKT (29). This was confirmed by Northern blotting (Fig.…”

mentioning

confidence: 55%

Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α

Campbell¹,

Bhat‐Nakshatri

Patel³

et al. 2001

Journal of Biological Chemistry

889

659

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Estrogen receptors (ERs) mediate most of the biological effects of estrogen in mammary and uterine epithelial cells by binding to estrogen response elements in the promoter region of target genes or through protein-protein interactions. Anti-estrogens such as tamoxifen inhibit the growth of ER-positive breast cancers by reducing the expression of estrogen-regulated genes. However, anti-estrogen-resistant growth of ER-positive tumors remains a significant clinical problem. Here we show that phosphatidylinositol (PI) 3-kinase and AKT activate ER␣ in the absence of estrogen. Although PI 3-kinase increased the activity of both estrogen-independent activation function 1 (AF-1) and estrogendependent activation function 2 (AF-2) of ER␣, AKT increased the activity of only AF-1. PTEN and a catalytically inactive AKT decreased PI 3-kinase-induced AF-1 activity, suggesting that PI 3-kinase utilizes AKTdependent and AKT-independent pathways in activating ER␣. The consensus AKT phosphorylation site Ser-167 of ER␣ is required for phosphorylation and activation by AKT. In addition, LY294002, a specific inhibitor of the PI 3-kinase/AKT pathway, reduced phosphorylation of ER␣ in vivo. Moreover, AKT overexpression led to up-regulation of estrogen-regulated pS2 gene, Bcl-2, and macrophage inhibitory cytokine 1. We demonstrate that AKT protects breast cancer cells from tamoxifen-induced apoptosis. Taken together, these results define a molecular link between activation of the PI 3-kinase/AKT survival pathways, hormone-independent activation of ER␣, and inhibition of tamoxifen-induced apoptotic regression.

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mentioning

confidence: 55%

Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α

Campbell¹,

Bhat‐Nakshatri

Patel³

et al. 2001

Journal of Biological Chemistry

889

659

View full text Add to dashboard Cite

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“…14 The secreted mature protein is a 25-kDa dimer cleaved from the 62-kDa intracellular precursor. 6 The production of biologically active GDF-15 is remarkably complex, and variability in the pool of available GDF-15 forms was suggested to be involved in modulating the tumor microenvironment when differences in GDF-15 expression between malignant and normal tissues were described. The premature proprotein is produced preferentially by cancer cells over normal tissues, and the preprocessed or mature GDF-15 forms have been suggested to be differentially deposited in extracellular matrix (ECM).…”

Section: Gdf-15 Sequence and Structurementioning

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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“…Macrophage inhibitory cytokine-1 (MIC-1), also known as placental bone morphogenetic protein, prostate-derived factor, and growth/differentiation factor 15, MIM#605312, is a member of the transforming growth factor-h superfamily that regulates a wide variety of physiologic processes involved in tissue differentiation and maintenance (1). A potential function is inhibition of macrophage activation (required for cell immune and inflammatory responses) in response to proinflammatory monokines (2).…”

Section: Introductionmentioning

confidence: 99%

Macrophage Inhibitory Cytokine-1 H6D Polymorphism, Prostate Cancer Risk, and Survival

Hayes

Severi

Southey³

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Macrophage inhibitory cytokine-1 (MIC-1), a member of the transforming growth factor-B superfamily, is important in regulating inflammation. Inflammation of the prostate has been suggested to favor tumor development. A recent study (JNCI 2004(JNCI , 96:1248(JNCI -1254 found marginal evidence of an association between the presence of the mature MIC-1 protein nonsynonymous polymorphism H6D C-to-G (rs1058587) with reduced prostate cancer risk [odds ratio, 0.83; 95% confidence interval (95% CI), 0.69-0.99]. We tested this in a population-based study of 819 cases and 731 controls from Australia and found a similar, yet not significant, odds ratio of 0.85 (95% CI, 0.7-1.04; P = 0.11).We also tested the potential association between the H6D variant and disease-specific survival in 640 cases followed-up for an average of 8.2 years. We found that cases carrying the H6D G allele had an increased risk of death from prostate cancer than cases carrying two copies of the C allele (hazard ratio, 1.72; 95% CI, 1.06-2.78; P = 0.03). Our data suggest that the H6D variant in MIC-1 might play a role in prostate cancer, but it is difficult to explain how a variant can be associated with lower risk of developing prostate cancer but more aggressive growth if cancer develops. (Cancer Epidemiol Biomarkers Prev 2006;15(6):1223 -5)

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MIC-1 is a novel TGF-β superfamily cytokine associated with macrophage activation

Cited by 231 publications

References 9 publications

Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α

Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α

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

Macrophage Inhibitory Cytokine-1 H6D Polymorphism, Prostate Cancer Risk, and Survival

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