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PubMed2005

A disintegrin and metalloprotease 33 polymorphisms and lung function decline in the general population.

RATIONALE: A disintegrin and metalloprotease 33 (ADAM33) has been identified as a susceptibility gene for asthma and single nucleotide polymorphisms (SNPs) in this gene have been associated with excessive decline of lung function in individuals with asthma. OBJECTIVES: To assess whether SNPs in ADAM33 are associated with accelerated lung function loss in the general population and with chronic obstructive pulmonary disease (COPD). METHODS: DNA was collected from subjects of the Vlagtwedde-Vlaardingen cohort participating in the last survey in 1989-1990 after a follow-up of 25 years. Information was collected every 3 years, including lung function measurements. We defined COPD as GOLD stage 2 or higher at the last survey. A total of 1,390 subjects from the cohort was genotyped for the following SNPs in ADAM33: F+1, Q-1, S_1, S_2, T_1, T_2, V_4, and ST+5. Differences in prevalence of SNPs were analyzed with chi(2) tests. Linear mixed effects models were used to analyze FEV(1) decline according to genotype. MEASUREMENTS AND MAIN RESULTS: In the whole population, mean adjusted decline was 18.7 and 12.7 ml/year in females and males, respectively. Individuals homozygous for minor alleles of SNPs S_2 and Q-1 and heterozygous for SNP S_1 had a significantly accelerated decline in FEV(1) of, respectively, 4.9, 9.6, and 3.6 ml/year compared with wild type. We found a significantly higher prevalence of SNPs F+1, S_1, S_2, and T_2 in subjects with COPD. CONCLUSIONS: We demonstrated that SNPs in ADAM33 are associated with accelerated lung function decline in the general population. These SNPs are also risk factors for COPD.

ADAM Proteins↗
PubMed2004

Expression and regulation of a disintegrin and metalloproteinase (ADAM) 8 in experimental asthma.

Asthma, a complex chronic inflammatory pulmonary disorder, is on the rise despite intense ongoing research. To elucidate novel pathways involved in asthma pathogenesis, we used transcript expression profiling in a murine model of asthma. Employing asthma models induced by different allergens (ovalbumin and Aspergillus fumigatus) we uncovered the involvement of ADAM8, a member of a disintegrin and metalloproteinase (ADAM) family. In situ hybridization of mouse lungs revealed strong ADAM8 induction in peribronchial and perivascular inflammatory cells as well as in bronchiolar epithelial cells following allergen challenge. Sequence analysis of lung ADAM8 cDNA identified a novel splice variant of ADAM8 that contained an additional exon in juxtaposition to the transmembrane domain. Allergen-induced ADAM8 mRNA accumulation in the lung was dose- and time-dependent. Transgenic or pharmacologic delivery of interleukin (IL)-4 or IL-13 to the lungs resulted in a marked increase of ADAM8 expression. Gene-targeted mice studies revealed that ovalbumin-induced ADAM8 was largely dependent upon signal transducer and activator of transcription (STAT) 6 and the IL-4 receptor alpha-chain. Thus, ADAM8 is an allergen-, IL-4-, and IL-13-induced gene in the experimental asthmatic lung. Taken together with the role of ADAM33 in asthma, these results suggest that allergic lung responses involve the interplay of diverse members of the ADAM family.

ADAM Proteins↗
PubMed2003

The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion.

The CX3C chemokine fractalkine (CX3CL1) exists as a membrane-expressed protein promoting cell-cell adhesion and as a soluble molecule inducing chemotaxis. Transmembrane CX3CL1 is converted into its soluble form by defined proteolytic cleavage (shedding), which can be enhanced by stimulation with phorbol-12-myristate-13-acetate (PMA). PMA-induced CX3CL1 shedding has been shown to involve the tumor necrosis factor-alpha-converting enzyme (TACE), whereas the constitutive cleavage in unstimulated cells remains elusive. Here we demonstrate a role of the closely related disintegrin-like metalloproteinase 10 (ADAM10) in the constitutive CX3CL1 cleavage. The hydroxamate GW280264X, capable of blocking TACE as well as ADAM10, proved to be an effective inhibitor of the constitutive and the PMA-inducible CX3CL1 cleavage in CX3CL1-expressing ECV-304 cells (CX3CL1-ECV-304), whereas GI254023X, preferentially blocking ADAM10 but not TACE, reduced the constitutive cleavage only. Overexpression of ADAM10 in COS-7 cells enhanced constitutive cleavage of CX3CL1 and, more importantly, in murine fibroblasts deficient of ADAM10 constitutive CX3CL1 cleavage was markedly reduced. Thus, ADAM10 contributes to the constitutive shedding of CX3CL1 in unstimulated cells. Addressing the functional role of CX3CL1 shedding for the adhesion of monocytic cells via membrane-expressed CX3CL1, we found that THP-1 cells adhere to CX3CL1-ECV-304 cells but detach in the course of vigorous washing. Inhibition of ADAM10-mediated CX3CL1 shedding not only increased adhesive properties of CX3CL1-ECV-304 cells but also prevented de-adhesion of bound THP-1 cells. Our data demonstrate that ADAM10 is involved in the constitutive cleavage of CX3CL1 and thereby may regulate the recruitment of monocytic cells to CX3CL1-expressing cell layers.

ADAM Proteins↗
PubMed1997

ADAM7, a member of the ADAM (a disintegrin and metalloprotease) gene family is specifically expressed in the mouse anterior pituitary and epididymis.

The maturation of spermatozoa in the epididymis is a complex process that requires the active involvement of the epididymal epithelium. The primary focus toward elucidating the role of the epididymis in the maturation process has been the study of epididymal secretory proteins and their interaction with spermatozoa. To date there is a paucity of information regarding epididymal epithelial cell surface proteins, which may also play important roles in epididymal function. Through a subtractive hybridization approach to identify genes specifically expressed in the caput epididymidis, the mouse homologue of a member of the ADAM (a disintegrin and metalloprotease) family of proteins was identified. This rapidly growing gene family encodes cell surface proteins that possess putative adhesion and protease domains. Northern blot analyses demonstrated that the mouse ADAM gene, termed ADAM7, is expressed in the caput region of the epididymis and in the anterior pituitary gonadotropes with no detectable expression in the twenty-six other tissues examined. Furthermore, in situ hybridization experiments revealed that the ADAM7 messenger RNA (mRNA) exhibited an apical localization within the proximal caput epididymal epithelium that may correlate with an unusual sparsely granulated endoplasmic reticulum uniquely present in the proximal region of the epididymidis and to which no known function has been ascribed. Hormonal, surgical, and genetic strategies demonstrated that ADAM7 gene expression requires, in a region-dependent manner, androgens as well as testicular factors for expression. Interestingly, the apical localization of ADAM7 mRNA is dependent upon an intact testis, because in situ hybridization analyses of the proximal caput epididymidis from a testosterone maintained castrate mouse did not show the apical localization of ADAM7 mRNA. Finally, chromosomal mapping demonstrated that the ADAM7 gene maps to the central region of mouse Chromosome 14, approximately 4-5 cM distal from the fertilin beta locus, which encodes another reproductive-specific ADAM protein.

ADAM Proteins↗
PubMed2006

Regulation of A Disintegrin And Metalloproteinase with ThromboSpondin repeats-1 expression in human endometrial stromal cells by gonadal steroids involves progestins, androgens, and estrogens.

CONTEXT: Gonadal steroids are key regulators of the extracellular matrix remodeling events that occur in the human endometrium during each menstrual cycle. The spatiotemporal expression of A Disintegrin And Metalloproteinase with ThromboSpondin repeats (ADAMTS)-1 in human endometrial stroma in vivo suggests that this novel metalloproteinase may contribute to this tightly regulated developmental process. OBJECTIVE: The objective of the study was to determine whether progesterone (P4), 17beta-estradiol (E2), or the nonaromatizable androgen dihydrotestosterone (DHT), alone or in combination, is capable of regulating ADAMTS-1 mRNA and protein levels in human endometrial stromal cells in a concentration- and time-dependent manner. DESIGN: A real-time quantitative PCR strategy and Western blotting were used to examine ADAMTS-1 mRNA and protein expression levels in primary cultures of human endometrial stromal cells. RESULTS: P4 and DHT but not E2 increased the levels of the ADAMTS-1 mRNA transcript and protein species (110 kDa) present in endometrial stromal cells in vitro in a concentration- and time-dependent manner. A combination of P4 and DHT resulted in an additional increase in stromal ADAMTS-1 expression, whereas E2 attenuated the regulatory effects of P4 and DHT in a concentration-dependent manner. The antisteroidal compounds, mifepristone (RU486) and hydroxyflutamide, were also found to inhibit specifically the P4- and DHT-mediated increase in ADAMTS-1 mRNA and protein expression levels in these primary cell cultures in a concentration-dependent manner, respectively. CONCLUSIONS: These studies demonstrate that progestins, androgens, and estrogens, alone and in combination, have distinct regulatory effects on ADAMTS-1 mRNA and protein expression levels in human endometrial stromal cells in vitro.

ADAM Proteins↗
PubMed2003

UNC-71, a disintegrin and metalloprotease (ADAM) protein, regulates motor axon guidance and sex myoblast migration in C. elegans.

The migration of cells and growth cones is a process that is guided by extracellular cues and requires the controlled remodeling of the extracellular matrix along the migratory path. The ADAM proteins are important regulators of cellular adhesion and recognition because they can combine regulated proteolysis with modulation of cell adhesion. We report that the C. elegans gene unc-71 encodes a unique ADAM with an inactive metalloprotease domain. Loss-of-function mutations in unc-71 cause distinct defects in motor axon guidance and sex myoblast migration. Many unc-71 mutations affect the disintegrin and the cysteine-rich domains, supporting a major function of unc-71 in cell adhesion. UNC-71 appears to be expressed in a selected set of cells. Genetic mosaic analysis and tissue-specific expression studies indicate that unc-71 acts in a cell non-autonomous manner for both motor axon guidance and sex myoblast migration. Finally, double mutant analysis of unc-71 with other axon guidance signaling molecules suggests that UNC-71 probably functions in a combinatorial manner with integrins and UNC-6/netrin to provide distinct axon guidance cues at specific choice points for motoneurons.

Alleles↗
PubMed2006

ADAM15 disintegrin is associated with aggressive prostate and breast cancer disease.

The aim of the current study was to evaluate the expression of ADAM15 disintegrin (ADAM15) in a broad spectrum of human tumors. The transcript for ADAM15 was found to be highly upregulated in a variety of tumor cDNA expression arrays. ADAM15 protein expression was examined in tissue microarrays (TMAs) consisting of 638 tissue cores. TMA analysis revealed that ADAM15 protein was significantly increased in multiple types of adenocarcinoma, specifically in prostate and breast cancer specimens. Statistical association was observed with disease progression within clinical parameters of predictive outcome for both prostate and breast cancers, pertaining to Gleason sum and angioinvasion, respectively. In this report, we also present data from a cDNA microarray of prostate cancer (PCa), where we compared transfected LNCaP cells that overexpress ADAM15 to vector control cells. In these experiments, we found that ADAM15 expression was associated with the induction of specific proteases and protease inhibitors, particularly tissue inhibitor of metalloproteinase 2, as validated in a separate PCa TMA. These results suggest that ADAM15 is generally overexpressed in adenocarcinoma and is highly associated with metastatic progression of prostate and breast cancers.

ADAM Proteins↗
PubMed2005

Metalloproteinase inhibitors for the disintegrin-like metalloproteinases ADAM10 and ADAM17 that differentially block constitutive and phorbol ester-inducible shedding of cell surface molecules.

The transmembrane metzinkin-proteases of the ADAM (a disintegrin and a metalloproteinase)-family ADAM10 and ADAM 17 are both implicated in the ectodomain shedding of various cell surface molecules including the IL6-receptor and the transmembrane chemokines CX3CL1 and CXCL16. These molecules are constitutively released from cultured cells, a process that can be rapidly enhanced by cell stimulation with phorbol esters such as PMA. Recent research supports the view that the constitutive cleavage predominantly involves ADAM10 while the inducible one is mediated to a large extent by ADAM17. We here describe the discovery of hydroxamate compounds with different potency against ADAM10 and ADAM17 and different ability to block constitutive and inducible cleavage of IL6R, CX3CL1 and CXCL16 by the two proteases. By screening a number of hydroxamate inhibitors for the inhibition of recombinant metalloproteinases, a compound was found inhibiting ADAM10 with more than 100-fold higher potency than ADAM17, which may be explained by an improved fit of the compound to the S1' specificity pocket of ADAM10 as compared to that of ADAM17. In cell-based cleavage experiments this compound (GI254023X) potently blocked the constitutive release of IL6R, CX3CL1 and CXCL16, which was in line with the reported involvement of ADAM10 but not ADAM17 in this process. By contrast, the compound did not affect the PMA-induced shedding, which was only blocked by GW280264X, a potent inhibitor of ADAM17. As expected, GI254023X did not further decrease the residual release of CX3CL1 and CXCL16 in ADAM10-deficient cells verifying that the compound's effect on the constitutive shedding of these molecules was exclusively due to the inhibition of ADAM10. Thus, GI254023X may by of use as a preferential inhibitor of constitutive shedding events without effecting the inducible shedding in response to agonists acting similar to PMA.

ADAM Proteins↗
PubMed1999

A novel disintegrin salmosin inhibits tumor angiogenesis.

Salmosin is a snake venom-derived novel disintegrin that antagonizes platelet aggregation. In this study, we investigated its functional specificity in tumor angiogenesis. Salmosin significantly inhibited bovine capillary endothelial cell proliferation induced by basic fibroblast growth factor but had no effect on normal growth of the cell. The basic fibroblast growth factor-induced in vivo angiogenesis in the chorioallantoic membrane was disrupted by salmosin treatment without affecting normal embryonic angiogenesis. Adhesion of the bovine capillary endothelial cells to vitronectin was also inhibited by the binding of salmosin to the alpha(v)beta3 integrin. Both the metastatic-tumor growth and the solid-tumor growth that developed in mice were effectively suppressed by salmosin treatment. Several lines of experimental evidence strongly suggest that the tumor-specific antiangiogenic activity of salmosin disrupts tumor growth by blocking the alpha(v)beta3 integrin that is expressed on the vascular endothelial cell surface.

Allantois↗
PubMed2001

Cloning, Expression and Antibody Production of the Disintegrin Domain of Human Fertilin beta.

A cDNA for the disintegrin domain (hf279) was isolated by PCR from human testis cDNAs. DNA sequencing indicated that hf279 cDNA encoded 93 amino acid residues, and it was identical with the reported sequence of fertilin beta. An expression plasmid, pGEX hf279, was constructed by inserting hf279 cDNA into plasmid pGEX-4T-2 containing gst gene. The expression plasmid was introduced into E.coli BL21(DE3) cells and a substantial amount of soluble fused protein GST-HF93 was obtained by the expression strain HF93/BL21 induced with IPTG. SDS-PAGE analysis revealed that the GST-HF93 fusion protein had an apparent molecular weight of 38 kD and accumulated up to 50% of bacterial soluble proteins. The fusion protein was purified by glutathione S-transferase (GST) Sepharose 4B column (purity 90%) and digested by thrombin to obtain the purified HF93 peptide (purity 80%). Polyclonal antibodies were obtained from the serum of miceimmunized with purified HF93 which was isolated by GST Sepharose 4B column and SDS-PAGE. ELISA and Western blot analysis showed its specificity to HF93. Therefore this antibody can be used in further studies on the function of HF93.

Journal Article↗
PubMed2004

[Expression of a disintegrin-like and metalloproteinase protein 8 and 12 in the giant cell lesions of jaw].

OBJECTIVE: To detect the expression of a disintegrin-like and metalloproteinase (ADAM) 8 and 12 gene in the giant cell lesions of jaw and to study their effects on the histogenesis of cells in these lesions. METHODS: ADAM8 and ADAM12 was detected by immunohistochemistry (SP) in 40 paraffin-embedded specimens of central giant cell lesions of jaw, 10 peripheral giant cell lesions, 9 cherubisms, 6 aneurysmal bone cysts. RESULTS: ADAM8 and ADAM12 were positive in the cytomembrane and cytoplasm of all multinucleated giant cells and some round mononuclear cells of the lesions; ADAM12 was positive for some spindle mononuclear stromal cells in central and peripheral giant cell lesions. CONCLUSIONS: Multinucleated giant cells probably originated from the fusion of the round mononuclear cells, and ADAM8 and ADAM12 were involved in this process. In addition, ADAM12 might play a role in the maturation of spindle mononuclear stromal cells.

ADAM Proteins↗
PubMed2005

[Expression of macrophage inflammatory protein-1alpha, a disintegrin-like and metalloproteinase 8 and 12, and CD68 protein in giant cell lesions of jaw and giant cell tumors of long bone].

OBJECTIVE: To detect the expression of macrophage inflammatory protein-1alpha (MIP-1alpha), a disintegrin-like and metalloproteinase (ADAM) 8 and 12 and CD68 protein in giant cell lesions of jaw and giant cell tumors of long bone, and to study their effects on the histogenesis of giant cells in such lesions. METHODS: MIP-1alpha, ADAM8, ADAM12 and CD68 were detected by immunohistochemistry in 24 paraffin-embedded specimens of central giant cell lesions of jaw and giant cell tumors respectively. RESULTS: MIP-1alpha positive signal was located in blood vessels and bone. ADAM8, ADAM12 and CD68 positive signals were located in the cell membrane and cytoplasm of all multinucleated giant cells and some round mononuclear cells in the lesions. In addition, some spindle mononuclear stromal cells were positive for ADAM12 in both lesions. CONCLUSION: Multinucleated giant cells probably originate from CD68-postive round mononuclear cells, which are recruited from monocyte-macrophage system by chemokines, such as MIP-1alpha, followed by cell fusion mediated by ADAM8 and ADAM12.

ADAM Proteins↗
PubMed1992

Coagulation factor X activating enzyme from Russell's viper venom (RVV-X). A novel metalloproteinase with disintegrin (platelet aggregation inhibitor)-like and C-type lectin-like domains.

We determined the complete amino acid sequence of RVV-X, the blood coagulation factor X activating enzyme, isolated from Russell's viper venom and studied structure-function relationships. RVV-X (M(r) 79,000) consists of a disulfide-bonded two-chain glycoprotein with a heavy chain of M(r) 59,000 and a light chain of heterogeneous M(r) 18,000 (LC1) and 21,000 (LC2). These chains were separated after reduction and S-pyridylethylation, and the isolated major component LC1 was used for sequence analysis. The heavy chain consists of 427 residues containing four asparagine-linked oligosaccharides, and its entire sequence was similar to that of the high molecular mass hemorrhagic protein, HR1B, isolated from the venom of Trimere-surus flavoviridis. The heavy chain contains three distinct domains, metalloproteinase, disintegrin (platelet aggregation inhibitor)-like and unknown cysteine-rich domains. On the other hand, light chain LC1 consists of 123 amino acid residues containing one asparagine-linked oligosaccharide and shows sequence homology similar to that found in the so-called C-type (Ca(2+)-dependent) lectins. Therefore, RVV-X is a novel metalloproteinase containing a mosaic structure with distintegrin-like, cysteine-rich, and C-type lectin-like domains. RVV-X potently inhibits collagen- and ADP-stimulated platelet aggregations, probably via its distintegrin-like domain, although this domain does not contain the Arg-Gly-Asp sequence which is conserved in various venom distintegrins and which is thought to be one of the interaction sites for platelet integrins. Our findings also indicate that snake venom factor IX/factor X-binding protein with a C-type lectin structure (Atoda, H., Hyuga, M., and Morita, T. (1991) J. Biol. Chem. 266, 14903-14911) inhibits RVV-X-catalyzed factor X activation; hence, the light chain of RVV-X probably participates in recognizing some portion of the zymogen factor X.

Amino Acid Sequence↗
PubMed2006

Interferon-gamma down-regulates expression of tumor necrosis factor-alpha converting enzyme/a disintegrin and metalloproteinase 17 in activated hepatic stellate cells of rats.

Interferon-gamma (IFN-gamma) is a potent cytokine that exerts antiproliferative and antifibrogenic effects on hepatic stellate cells (HSCs). Although therapeutic application of IFN-gamma for chronic liver diseases is anticipated, the responses of activated HSCs to IFN-gamma have not been fully elucidated. To seek unknown molecules and pathways that might be responsive to IFN-gamma treatment in activated HSCs, we examined global protein expression profiles using two-dimensional gel electrophoresis combined with peptide mass fingerprint. We identified 76 increased and 59 decreased spots (>3-fold increase or decrease, total 135 spots). Database analysis suggested that the following four pathways were involved in alteration of HSCs toward a quiescent phenotype in response to IFN-gamma: i) down-regulation of the TGF-beta and PDGF signaling pathways; ii) reorganization of intermediate filaments; iii) up-regulation of fatty acid metabolism; iv) decreased expression of TNF-alpha converting enzyme (TACE)/a disintegrin and metalloproteinase 17 (ADAM17), which is responsible for shedding of the proinflammatory cytokine TNF-alpha. We confirmed down-regulation of both ADAM17 expression and soluble TNF-alpha secretion by Western blotting and real-time PCR. TNF-alpha mRNA/protein expression was not altered by IFN-gamma treatment. Our data suggest that IFN-gamma stimulation suppresses the activated phenotype of HSCs in vitro through multiple pathways. Of these pathways, down-regulation of ADAM17 expression may play a role in blocking the auto-activation mechanism of cultured HSCs through activation of the TNF-alpha signaling and shedding pathways.

ADAM Proteins↗
PubMed1995

Echistatin, a disintegrin, inhibits sperm-oolemmal adhesion but not oocyte penetration.

OBJECTIVE: To study the effects of echistatin, a disintegrin known to block the binding of fibronectin (FN) and vitronectin to their respective integrin receptors, alpha 5 beta 1 and alpha v beta 3, on the adhesion of human spermatozoa to the oolemma of zona-free hamster eggs and their subsequent penetration. DESIGN: Motile capacitated human spermatozoa and zona-free hamster eggs were coincubated in the presence of echistatin or in its absence and observed at short serial intervals. Whole mounts of these eggs, washed out of sperm suspension and stained with acridine orange, were scored for numbers of oolemmal adherent and penetrating sperm. SETTING: University Hospital laboratories. PATIENTS: Known fertile semen donors. MAIN OUTCOME MEASURES: Numbers of spermatozoa adherent to the oolemma and those penetrating the oocyte. RESULTS: Sperm adherence to the oolemma was reduced significantly at micromolar concentrations of echistatin, in a concentration-dependent manner. In contrast, echistatin did not inhibit the penetration of oocytes by sperm that had become adherent to the oolemma despite the presence of echistatin. CONCLUSION: We propose that two processes occur in the binding of sperm to the oolemma, one that is echistatin sensitive and possibly involving the integrin receptors that recognize FN and vitronectin, and a second process, resistant to echistatin, that leads to gamete membrane fusion.

Animals↗
PubMed1996

Measurement of glycoprotein IIb/IIIa blockade by flow cytometry with fluorescein isothiocyanate-conjugated crotavirin, a member of disintegrins.

The blockade of platelet membrane glycoprotein IIb/IIIa by a monoclonal antibody, 7E3, was measured by flow cytometry using a fluorescein isothiocyanate-conjugated disintegrin, FITC-crotavirin, as the probe. After treatment of platelets with 7E3 or 7E3 F(ab')2, there is a good correlation between the inhibition of platelet aggregation and the blockade of FITC-crotavirin's binding to platelets. The content of glycoprotein IIb/IIIa for the subsequent binding of FITC-crotavirin to the 7E3-pretreated platelets highly correlated to the extent of glycoprotein IIb/IIIa, remaining available. It was evidenced by the observation that the sum of glycoprotein IIb/IIIa occupation by 7E3 and that of FITC-crotavirin approached the total amount of glycoprotein IIb/IIIa expressed on the platelet membrane. This indicates that the percentage inhibition of FITC-crotavirin's binding at the saturation dose reflects the extent of glycoprotein IIb/IIIa blockade by 7E3. At the saturation binding concentration (5 micrograms/ml), FITC-crotavirin did not displace platelet bound 7E3. Gating the light-scattering profile for platelets, the binding of FITC-crotavirin to platelet glycoprotein IIb/IIIa could be easily determined in diluted whole blood by direct stain method. The available unoccupied glycoprotein IIb/IIIa of platelets in the 7E3 or 7E3 F(ab')2-pretreated whole blood were measured by flow cytometry at the saturation binding dose of FITC-crotavirin (4 micrograms/ml) and the data showed that the higher deconcentration of antibody added into whole blood, the lower debinding of FITC-crotavirin to platelets. This technique may provide an alternative rapid method for measuring the blockade of glycoprotein IIb/IIIa by 7E3, a promising anti-thrombotic agent, thus providing a monitoring method for adjusting the therapeutic dose of 7E3 or its related derivatives.

Antibodies, Monoclonal↗
PubMed2004

Aberrant alternative exon use and increased copy number of human metalloprotease-disintegrin ADAM15 gene in breast cancer cells.

ADAM genes have been associated with cancer, with ADAM expression, genomic rearrangements, and, by implication of ADAM proteins in the altered behavior found in tumor cells. In the present study, increased copy number of the ADAM15 gene in human breast cancer cell lines was demonstrated by fluorescence in situ hybridization. This was not reflected in mRNA levels, however. Instead, the use of alternative ADAM15 exons appeared erratic, leading to aberrant combinations of ADAM15 mRNA isoforms in the cancer cells. Clustering analysis indicated that these isoform patterns were nonrandom, suggesting a failure in the regulation mechanism or mechanisms of the alternative exon usage. Altered regulation of alternative exon usage may provide a useful target for cancer diagnostics development. ADAM15 would be particularly appropriate for breast cancer diagnostics because the various combinations of its three alternatively used exons can be readily examined with a simple, straightforward PCR protocol.

ADAM Proteins↗