Transcriptional Activation of Mouse Mast Cell Protease-7 by Activin and Transforming Growth Factor-β Is Inhibited by Microphthalmia-associated Transcription Factor

Funaba, Masayuki; Ikeda, Teruo; Murakami, Masaru; Ogawa, Kenji; Tsuchida, Kunihiro; Sugino, Hiromu; Abe, Matanobu

doi:10.1074/jbc.m306991200

Cited by 49 publications

(33 citation statements)

References 62 publications

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“…Activin A m NO, IL-1b, PGE 2 , TXA 2 , TNF-a and IL-6, but in activated macrophages k NO and IL-1b 36,37,39 a , 41,47,49 Peritoneal macrophages and RAW264.7 cell line Activin A mphagocytosis and pinocytosis, but k these activities under activation conditions 37,41,47 Peritoneal macrophages and RAW264.7 cell line Activin A m MHC-II and CD80 expression, but k MHC-II, CD68, CD14 and TLR4 induced by LPS 37,41,47 Peritoneal macrophages Activin A m MMP2 production 38 Bone marrow-derived macrophages Activin A promotes osteoclastogenesis 45,46 In vivo Bone marrow-derived mast cell progenitors Activin A regulates cell growth and maturation of mast cells 58,59 Bone marrow-derived mast cell progenitors Activin A m cell migration and production of MCP-1, -6 and -7 59,60,61 In vivo…”

Section: In Vitromentioning

confidence: 99%

When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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Activins and inhibins are members of the transforming growth factor-b superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses. Keywords: activin; inhibin; inflammation; immune cells; immunity; tolerance Activins and inhibins are members of the transforming growth factor-b (TGF-b) superfamily that were initially described as regulators of reproductive processes in mammals, and were first named after their positive and negative effect in the release of follicle-stimulating hormone from the pituitary gland, respectively. 1 These dimeric ligands have been shown to modulate a variety of cellular functions such as apoptosis, proliferation, differentiation, cellular migration, among others. 2,3 Activin A (bA/bA) is the best-characterized ligand of this subfamily, although there are other bioactive forms, activin B (bB/bB) and activin AB (bA/bB), which differ in their potency and cellular function. 4 Activin A is a molecule with pleiotropic functions, which shares with TGF-b the SMAD2/3 canonical signaling pathway (reviewed by Shi and Massague 5 ) but uses distinct type II (ActRIIs) and type I (ALK2, ALK4 and ALK7) receptors. [6][7][8][9] The biological function of activins can be blocked by follistatin (FS), a glycoprotein that binds activin A with high affinity, functioning as a ligand trap. 10 On the other hand, inhibins are heterodimers formed by uncommon a-and b-subunits and exist in two isoforms, inhibin A (a/bA) and B (a/bB). Inhibins have been shown to antagonize activinmediated functions by a mechanism that involves binding to b-glycan (TGFbRIII) and formation of a ternary complex with ActRIIs. As a consequence, activin type I receptors (ALK4 and ALK2) are excluded from the receptor complex, leading to the inhibition of SMADmediated signaling. 3,[11][12][13][14] Despite the fact that inhibins have been classically considered as activin antagonists, there is evidence showing that they do not always antagonize activin-mediated functions in several cell types, suggesting the existence of an independent inhibinmediated signaling pathway. 3 Compelling evidence has shown that activins also regulate various non-reproductive processes, such as mesoderm induction, liver proliferation, skin morphogenesis, erythropoiesis, bone formation, neu...

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Section: In Vitromentioning

confidence: 99%

When versatility matters: activins/inhibins as key regulators of immunity

Alemán-Muench

Soldevila

2011

Immunol Cell Biol

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“…The pGL3-(CAGA)12-luciferase reporter containing the Smad-binding sequence (CAGA) was provided by C.-H. Heldin (Uppsala University, Uppsala, Sweden) (24). The pCMV-β-gal vector was used as described previously (43).…”

Section: Methodsmentioning

confidence: 99%

“…After an additional 24 hours, cells were lysed with ×1 lysis buffer (Promega), and luciferase activity in the cell lysates was determined by a luciferase reporter assay system (Promega) using an LB9506 MiniLumat Luminometer (Berthold Technologies). Luciferase activities were normalized by β-gal activity as described previously (43).…”

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confidence: 99%

Muscular atrophy of caveolin-3–deficient mice is rescued by myostatin inhibition

Ohsawa¹,

Hagiwara²,

Nakatani³

et al. 2006

J. Clin. Invest.

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101

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Caveolin-3, the muscle-specific isoform of caveolins, plays important roles in signal transduction. Dominant-negative mutations of the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy 1C (LGMD1C) with loss of caveolin-3. However, identification of the precise molecular mechanism leading to muscular atrophy in caveolin-3-deficient muscle has remained elusive. Myostatin, a member of the muscle-specific TGF-β superfamily, negatively regulates skeletal muscle volume. Here we report that caveolin-3 inhibited myostatin signaling by suppressing activation of its type I receptor; this was followed by hypophosphorylation of an intracellular effector, Mad homolog 2 (Smad2), and decreased downstream transcriptional activity. Loss of caveolin-3 in P104L mutant caveolin-3 transgenic mice caused muscular atrophy with increase in phosphorylated Smad2 (p-Smad2) as well as p21 (also known as Cdkn1a), a myostatin target gene. Introduction of the myostatin prodomain, an inhibitor of myostatin, by genetic crossing or intraperitoneal administration of the soluble type II myostatin receptor, another inhibitor, ameliorated muscular atrophy of the mutant caveolin-3 transgenic mice with suppression of p-Smad2 and p21 levels. These findings suggest that caveolin-3 normally suppresses the myostatin-mediated signal, thereby preventing muscular atrophy, and that hyperactivation of myostatin signaling participates in the pathogenesis of muscular atrophy in a mouse model of LGMD1C. Myostatin inhibition may be a promising therapy for LGMD1C patients.

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“…For this purpose, a TAP cDNA fragment cut by BamHI and SalI was subcloned into the BamHI and XhoI sites of hemagglutinin (HA)-pcDNA3 (9) to produce C-terminal HA-tagged protein. The plasmid or empty vector (HA-pcDNA3) was transiently transfected into COS7 cells, and at 48 h of transfection, cell lysates were collected as described previously (6). Western blot analyses using anti-TAP antiserum of cell lysates of COS7 cells overexpressing TAP revealed a significant band of the expected size (Fig.…”

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confidence: 99%

Expression of Tocopherol-Associated Protein in Mast Cells

Ikeda

Murakami

Funaba

2004

Clin Vaccine Immunol

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Tocopherol-associated protein (TAP) was expressed in mouse mast cells. TAP was predominantly localized in the cytoplasm, and the subcellular localization was not changed by ␣-tocopherol. The results suggest that the physiological role of TAP in mast cells is not regulation of tocopherol function but an as-yet-unidentified activity.In general, redox status modulates cellular functions. Oxidation stress activates cellular signaling, including the NF-B pathway and the mitogen-associated protein kinase pathway (2, 12). These reactions activate mast cells, leading to the release of inflammatory mediators, including tumor necrosis factor alpha (TNF-␣) and histamine (16,17). Vitamin E, a mixture of tocopherols and tocotrienols, is a lipid-soluble antioxidant that inhibits inflammatory reactions in vitro (12). Tocopherol-associated protein (TAP) is a cytosolic protein that associates with ␣-tocopherol with high affinity (19). Treatment with ␣-tocopherol resulted in nuclear translocation of TAP overexpressed in COS7 cells, and TAP acted as a transcriptional regulator in an ␣-tocopherol-dependent manner (18). These results suggest that TAP plays a crucial role in the intracellular metabolism and function of tocopherol (12). In the present paper, we report on the expression of TAP in mast cells. In contrast to the results obtained with COS7 cells (18), it was found that subcellular localization of endogenous TAP in mast cells is not regulated by ␣-tocopherol. This result suggests that the physiological role of TAP in mast cells is not regulation of tocopherol function but an as-yet-unidentified activity.Gene expression of a human TAP homologue in mouse mast cells was examined first. Total RNA was isolated from primary cultures of mouse mast cells, mouse mast cell lines, and mouse melanoma cells, and reverse transcription-PCR analyses were performed as described previously (10). PCR primers for the glyceraldehyde-3-phosphate dehydrogenase gene, a housekeeping gene, were described previously (3, 11). For the mouse TAP gene transcript (GenBank accession no. BC005759), oligonucleotides coding for nucleotide positions 758 through 778 and 1162 through 1141 were used as PCR primers. The PCR products were separated on 2% agarose gels in 1ϫ Tris-acetate EDTA buffer and visualized with ethidium bromide. Gene expression of TAP was detected in primary cultured cells, including bone marrow-derived cultured mast cell progenitors (BMCMCs) and cultured mast cells from mi/mi mice (Fig. 1A). In addition, TAP expression was detected in mast cell lines (MC/9, IC-2, and P-815) and melanoma cells (B-16), although the expression in MC/9 cells tended to be lower (Fig. 1A).To examine expression of TAP in mast cells at the protein level, antiserum directed against TAP was generated. A synthetic peptide spanning amino acids 1 to 11 of mouse TAP, coupled to keyhole limpet hemocyanin with glutaraldehyde, was administered to New Zealand White rabbits as described previously (4, 5). The reactivity of antiserum was monitored by enzyme-linked immunosorben...

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Transcriptional Activation of Mouse Mast Cell Protease-7 by Activin and Transforming Growth Factor-β Is Inhibited by Microphthalmia-associated Transcription Factor

Cited by 49 publications

References 62 publications

When versatility matters: activins/inhibins as key regulators of immunity

When versatility matters: activins/inhibins as key regulators of immunity

Muscular atrophy of caveolin-3–deficient mice is rescued by myostatin inhibition

Expression of Tocopherol-Associated Protein in Mast Cells

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