Female sterility in mice lacking the <i>basigin</i> gene, which encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily

Kuno, Naohiko; Kadomatsu, Kenji; Fan, Qi‐Wen; Hagihara, Mao; Senda, Toshiya; Mizutani, Shigehiko; Muramatsu, Takashi

doi:10.1016/s0014-5793(98)00213-0

Cited by 110 publications

(102 citation statements)

References 30 publications

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“…Furthermore, various physiological processes, such as proliferation and differentiation of epithelial cells, [47][48][49] fertilization, 18 differentiation and activation of immune cells, 10,50,51 integrin-mediated adhesion of myocytes of the left heart ventricle to basement membrane components, 52 selective transport processes in endothelial cells to maintain blood-brain-barrier function, 15 erythrocyte maturation 53 or wound healing 54 might also be influenced by an anti-EMMPRIN therapy.…”

Section: Discussionmentioning

confidence: 99%

“…16 Moreover, EMM-PRIN knockout mice are often sterile or present with deficiencies in spermatogenesis and fertilization. 17,18 To assess its putative role as a target for anticancer therapies, we analyzed the overall incidence of EMMPRIN expression in a wide spectrum of normal and tumor tissues. Our findings demonstrate a more frequent expression of EMMPRIN in cancerous than in normal tissues.…”

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confidence: 99%

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High incidence of EMMPRIN expression in human tumors

Riethdorf

Reimers

Assmann

et al. 2006

Intl Journal of Cancer

205

172

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Extracellular matrix metalloproteinase inducer expressed by tumor cells stimulates peritumoral fibroblasts to produce matrix metalloproteinases, thus contributing to tumor invasion and metastasis. To assess its suitability as potential therapeutic target, the overall incidence of EMMPRIN expression in normal and neoplastic tissues was analyzed. EMMPRIN expression was detected immunohistochemically using monoclonal antibodies MEM-M6/1 and HIM6 and tissue microarrays with 2,348 and 608 tissue samples from 129 distinct tumor types and 76 different normal tissues, respectively. Expression and glycosylation state of EMMPRIN in human breast cancer cells were analyzed by Western blot analysis with monoclonal antibodies recognizing distinct carbohydrate structures and biochemical methods. EMMPRIN expression was found in 112 of 129 tumor entities analyzed with malignant tumors being EMMPRIN positive more frequently than benign tumors. A remarkable heterogeneity in EMMPRIN expression between tumor entities was observed. Among others, squamous-cell carcinomas (60-100%), pancreatic (87%), chromophobic kidney (83%), hepatocellular (83%) or medullary breast (83%) adenocarcinomas as well as glioblastoma multiforme (79%) presented with a particular high incidence of EMMPRIN expression. There were a limited number of EMMPRIN-positive normal cell types including proliferatively active and differentiating epithelial cells, germ cells, myocardial cells in the left heart ventricle or vascular endothelial cells of the brain. We could further demonstrate that breast cancer cells expressed EMMPRIN isoforms differing in the presence or absence of Lewis X glycan structures. Our results may assist in defining the suitability of EMMPRIN as therapeutic target and predicting negative side effects. ' 2006 Wiley-Liss, Inc.Key words: extracellular matrix metalloproteinase inducer expression; human normal tissues; human tumors; glycosylation Tumor cell invasion and metastasis requires degradation of extracellular matrix components, which is mainly achieved by various proteolytic enzymes including zinc-dependent matrix metalloproteinases (MMPs). Analysis of MMP expression patterns in tumor specimens revealed that the majority of these enzymes are produced by stromal cells surrounding the tumor rather than by tumor cells themselves. An increasing body of evidence, however, suggests that MMP synthesis is stimulated by tumor cells in a paracrine fashion. This stimulation is at least partially attributed to extracellular matrix metalloproteinase inducer (EMMPRIN, also designated CD147 or basigin), a 58 kDa surface glycoprotein of the immunoglobulin superfamily, originally purified from the plasma membrane of cancer cells. 1 EMMPRIN has been demonstrated to stimulate production of MMP-1, -2, -3, -9, -14, -15 in fibroblasts surrounding tumor cells. 2 As shown by Sun and Hemler, 3 EMMPRIN also appears to participate in the induction of MMP production in tumor cells in an autocrine fashion. Accordingly, MDA-MB-436 human breast cancer cells recombinantly...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

High incidence of EMMPRIN expression in human tumors

Riethdorf

Reimers

Assmann

et al. 2006

Intl Journal of Cancer

205

172

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“…Total cell number used in condition Aa and Ab was the same (1 Â 10 7 cells). Bsg has been localized to the plasma membrane by immunohistochemical staining in the uterus, testis and pigment epithelia [24,30,31]. To confirm that the mature form is located on the cell surface, cell surface biotinylation was carried out on mouse Bsg-HA-transfected COS-7 cells, followed by immunoprecipitation with anti-HA Ig and immunoblotting with HRP-conjugated streptavidin.…”

Section: Characterization Of the Mature Form Of Bsgmentioning

confidence: 99%

Homo‐oligomer formation by basigin, an immunoglobulin superfamily member, via its N‐terminal immunoglobulin domain

Yoshida¹,

Shibata²,

Yamamoto³

et al. 2000

European Journal of Biochemistry

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Basigin (Bsg) is a highly glycosylated transmembrane protein with two immunoglobulin (Ig)-like domains. A number of studies, including gene targeting, have demonstrated that Bsg plays pivotal roles in spermatogenesis, implantation, neural network formation and tumor progression. In the present study, to understand the mechanism of action of Bsg, we determined its expression status on the plasma membrane. Cotransfection of Bsg expression vectors with two different tags clarified that Bsg forms homo-oligomers in a cis-dependent manner on the plasma membrane. If the disulfide bond of the more N-terminally located Ig-like domain was destroyed by mutations, Bsg could not form oligomers. In contrast, the mutations of the C-terminal Ig-like domain or N-glycosylation sites did not affect the association. The association of mouse and human Bsgs, which exhibit high homology in the transmembrane and intracellular domains but low homology in the extracellular domain, was very weak as compared with that within the same species, suggesting the importance of the extracellular domain in the association. If the extracellular domain of the human Ret protein was replaced with the N-terminal Ig-like domain of Bsg, the resulting chimera protein was associated with intact wild-type Bsg, but not if the C-terminal Ig-like domain, instead of the N-terminal one, of Bsg was used. No oligomer formation took place between the intact wild-type Ret and Bsg proteins. In conclusion, these data indicate that the N-terminal Ig-like domain is necessary and sufficient for oligomer formation by Bsg on the plasma membrane.Keywords: basigin; EMMPRIN; immunoglobulin superfamily; neurothelin; oligomer.Cell-surface proteins, such as the Ig superfamily, the cadherin superfamily and the integrin superfamily, play important roles in development by regulating cellular differentiation, adhesion and migration [1,2]. Supramolecular structure formation, such as oligomer formation, between these molecules plays crucial roles in exerting their functions. This has been documented by extensive studies of the Ig superfamily. NCAM participates in neural cell adhesion, which is mainly mediated by homophilic binding in a trans-dependent manner through its third Ig-like domain [3,4]. Homodimer formation of ICAM in a cis-dependent manner enhances its binding to a leukocyte b2-integrin [5]. Binding of fibroblast growth factor (FGF) to its receptor (FGFR) leads to dimer formation of FGFR (eventually a complex formation consisting of two FGF, two FGFR and a heparan sulfate chain), which is mediated mainly through homophilic binding at the second Ig-like domain of FGFR [6]. In addition to protein±protein interaction as mentioned above, protein±sugar interaction is also important. P0, a neural adhesion molecule implicated in myelination, harbors an N-glycosylation site, to which the major homophilic binding site is mapped [7]. NCAM and L1, another neural adhesion molecule, associate each other in a cis-dependent manner to reinforce L1 homophilic trans-interaction: in this case...

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“…Mice lacking the gene for CD147/EMMPRIN (called basigin in mice) showed defects in spermatogenesis and female fertilization (21,22), an altered mixed lymphocyte reaction, and loss of an aversive response to a strong odor (23). A cytotoxic antibody to CD147 has shown promising results in the treatment of graft versus host disease, presumably by selectively targeting activated B and T lymphocytes (24).…”

mentioning

confidence: 99%

Caveolin-1 Regulates Matrix Metalloproteinases-1 Induction and CD147/EMMPRIN Cell Surface Clustering

Tang

Hemler

2004

Journal of Biological Chemistry

137

125

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CD147, a regulator of matrix metalloproteinase (MMP) production, showed highly specific association with caveolin-1 on the surface of multiple cell types. CD147-caveolin-1 complex formation was temperature and cholesterol dependent, reminiscent of associations seen within caveolae/lipid rafts. However, the subset of caveolin-1 associated with CD147 appeared exclusively within intermediate density sucrose gradient fractions, rather than in the low density fractions containing the bulk of caveolin-1. Mutagenesis experiments revealed that CD147 Ig domain 2 was required for caveolin-1 association. In contrast to CD147-caveolin-1 complexes, CD147-␣ 3 integrin association was not disrupted upon cholesterol depletion, occurred in high density sucrose fractions, and did not involve CD147 Ig domain 2. Overexpression of caveolin-1 caused a specific decrease in clustering of cell surface CD147, as detected by "cluster specific" mAb M6/13. Conversely, a mutant CD147 deficient in caveolin-1 association showed enhanced spontaneous cell surface clustering (detected by mAb M6/13), and did not show decreased clustering in response to caveolin-1 overexpression. Furthermore, the same CD147 mutant yielded an elevated induction of MMP-1. In conclusion, caveolin-1 associates with CD147, in a complex distinct from CD147-␣ 3 integrin complexes, thereby diminishing both CD147 clustering and CD147-dependent MMP-1-inducing activity.Stromal fibroblasts secrete multiple matrix metalloproteinases (MMP) 1 that can promote tumor cell growth, survival, invasion, angiogenesis, and metastasis (1-3). A search for MMP-inducing tumor cell factors led to discovery and characterization of CD147/EMMPRIN (4,5). This molecule, on the surface of carcinoma cells or in recombinant soluble form, stimulates production of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), and MMP-3 (stromelysin) but not TIMP-1 (4 -7). The name "EMMPRIN" reflects the extracellular matrix metalloproteinase inducer activity of CD147. CD147 expression is often elevated on human tumor cells (4,8,9) and correlates with glioma tumor progression (10), hepatoma metastasis (11), and squamous cell carcinoma invasion, MMP-2 production, and extracellular matrix degradation (12). On melanoma cells, elevated CD147 promotes MMP-1, MMP-2, and MMP-3 production, and invasion through basement membrane (13,14), whereas overexpression of CD147 in a breast cancer cell line stimulated MMP-2 and MMP-9 production, and tumor growth and metastasis in nude mice (15). In summary, CD147 on tumor cells stimulates MMP production by stromal cells and/or other tumor cells, thereby leading to extracellular matrix degradation, and elevated tumor growth and metastasis. The MMP-inducing functions of CD147 at least partly involve CD147 acting as a counter-receptor for itself (16).Also, CD147 stimulates production of MMP-1 and MMP-3 in rheumatoid synovial tissue (17), and may facilitate erythrocyte circulation (18), and development of the thymus (19) and retina (20). Mice lacking the gene for CD147/EMMPRIN (call...

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Female sterility in mice lacking the basigin gene, which encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily

Cited by 110 publications

References 30 publications

High incidence of EMMPRIN expression in human tumors

High incidence of EMMPRIN expression in human tumors

Homo‐oligomer formation by basigin, an immunoglobulin superfamily member, via its N‐terminal immunoglobulin domain

Caveolin-1 Regulates Matrix Metalloproteinases-1 Induction and CD147/EMMPRIN Cell Surface Clustering

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