Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
1.
Atherosclerosis ; 218(1): 127-33, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21640993

ABSTRACT

OBJECTIVE: The single nucleotide polymorphism (SNP) rs2995300 in the metalloproteinase-disintegrin gene ADAM8 has been shown to affect the areas of complicated coronary plaques and the risk of fatal myocardial infarction (MI) in men. This study was set up to further investigate the role of ADAM8 in MI. AIM: To investigate the possible association of the ADAM8 SNPs rs2995300 and rs2275725 with ADAM8 mRNA levels, serum soluble ADAM8 (sADAM8) concentrations, and MI risk. METHODS: Samples from the Finnish cardiovascular study (FINCAVAS, N=2156) and the angiography and genes study (ANGES, N=1000) were genotyped. Serum sADAM8 concentrations were determined with ELISA (N=443). ADAM8 mRNA levels in atherosclerotic plaques were analysed from the tampere vascular study (TVS, N=53) samples. RESULTS: A significantly increased MI risk for carriers of the rs2995300C allele and the rs2275725 A allele was revealed in the meta-analysis of the ANGES and FINCAVAS patient data (OR=1.42, P<0.001 and OR=1.43, P<0.001). The risk increase was comparable to that caused by smoking in these cohorts. The risk allele carriers also had higher sADAM8 serum concentrations. CONCLUSIONS: The risk alleles of the investigated ADAM8 SNPs were associated with elevated sADAM8 serum levels and MI risk. The present results implicate ADAM8 in the development of CVDs and suggest its prognostic and therapeutic potential.


Subject(s)
ADAM Proteins/blood , ADAM Proteins/genetics , Gene Expression Regulation , Membrane Proteins/blood , Membrane Proteins/genetics , Myocardial Infarction/genetics , Aged , Alleles , Cohort Studies , Enzyme-Linked Immunosorbent Assay/methods , Female , Finland , Genetic Variation , Genotype , Heterozygote , Humans , Male , Middle Aged , Myocardial Infarction/metabolism , Phenotype , Prognosis , RNA, Messenger/metabolism , Risk
2.
J Cell Biochem ; 108(4): 877-85, 2009 Nov 01.
Article in English | MEDLINE | ID: mdl-19718658

ABSTRACT

A Disintegrin And Metalloprotease (ADAM15) is a member of the adamalysin protein family and has been associated with cancer, possibly via its role in ectodomain shedding of cadherins. Alternative mRNA splicing generates several ADAM15 isoforms containing different combinations of putative Src homology-3 (SH3) domain binding sites in their cytosolic tails. Here we present a comprehensive characterization of SH3 binding potential of different ADAM15 isoforms. Alternative use of ADAM15 exons was found to profoundly influence selection of SH3-containing cellular partner proteins, including the avid interactions with nephrocystin and sorting nexin-33 (SNX33 a.k.a. SNX30). Specifically, strong co-precipitation of nephrocystin from cell lysates was specific to ADAM15 isoforms i4, i5, and i6. These isoforms contain one or both of the two almost identical proline-rich regions encoded by exons 20 and 21, wherein the residues RxLPxxP were found to be indispensable for nephrocystin SH3 binding. Similarly, robust cellular association with SNX33 was observed only for ADAM15 isoforms containing the most carboxyterminal proline cluster lacking in isoforms i1 and i3. Thus, alternative mRNA splicing provides a versatile mechanism for regulation of intracellular protein interactions and thereby likely the cellular functions of ADAM15, which could explain the association with cancer of some but not all ADAM15 isoforms.


Subject(s)
ADAM Proteins/biosynthesis , ADAM Proteins/genetics , Adaptor Proteins, Signal Transducing/chemistry , Alternative Splicing , Carrier Proteins/chemistry , Membrane Proteins/biosynthesis , Membrane Proteins/chemistry , Membrane Proteins/genetics , Vesicular Transport Proteins/chemistry , Amino Acid Motifs , Cell Line , Cytoskeletal Proteins , Humans , Proline/chemistry , Promoter Regions, Genetic , Protein Binding , Protein Isoforms , Protein Structure, Tertiary , RNA, Messenger/metabolism , Sorting Nexins , src Homology Domains
3.
Ann Med ; 41(7): 497-507, 2009.
Article in English | MEDLINE | ID: mdl-19575316

ABSTRACT

OBJECTIVE: Previously, we scanned all 23,000 human genes for differential expression between normal and atherosclerotic tissues and found the involvement of ADAM8. METHODS: We investigated the expression of ADAM8 mRNA and protein level in human atherosclerotic tissues and non-atherosclerotic internal thoracic arteries as well as the association of ADAM8 2662 T/G single nucleotide polymorphism (SNP) with the extent of coronary atherosclerosis and with the risk of fatal myocardial infarction. RESULTS: ADAM8 mRNA was up-regulated in carotid, aortic, and femoral atherosclerotic plaques (n=24) when compared with non-atherosclerotic arteries. ADAM8 protein expression was increased in advanced atherosclerotic plaques as compared to control vessels wherein it was localized to macrophages and smooth muscle cells The G allele carriers of the ADAM8 2662 T/G SNP had significantly larger areas of fibrotic, calcified, and complicated plaques in coronary arteries (P=0.027, P=0.011, and P=0.011, respectively) and significantly higher occurrence of myocardial infarction (MI) (P=0.004) and fatal pre-hospital MI (P=0.003) than did the TT homozygotes. CONCLUSION: ADAM8 is a promising candidate to be involved in atherosclerosis, and its 2662 T/G allelic variant significantly associates with advanced atherosclerotic lesion areas and MI.


Subject(s)
ADAM Proteins/genetics , ADAM Proteins/metabolism , Atherosclerosis/genetics , Atherosclerosis/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Myocardial Infarction/genetics , Myocardial Infarction/mortality , Polymorphism, Single Nucleotide , Adult , Alleles , Atherosclerosis/epidemiology , Coronary Vessels/pathology , Finland/epidemiology , Gene Expression , Health Surveys/statistics & numerical data , Humans , Immunohistochemistry , Male , Middle Aged , Phenotype , RNA, Messenger/metabolism , Risk Factors , Statistics, Nonparametric , Up-Regulation/genetics
4.
Ann Med ; 41(4): 279-90, 2009.
Article in English | MEDLINE | ID: mdl-19253070

ABSTRACT

BACKGROUND AND AIMS: The expression of disintegrin and metalloprotease ADAM-9, ADAM-15, and ADAM-17 has been associated with cell-cell, cell-platelet, and cell-matrix interactions and inflammation. They are possibly implicated in the pathophysiology of atherosclerosis. METHODS AND RESULTS: Whole-genome expression array and quantitative real-time polymerase chain reaction (PCR) analysis confirmed that ADAM-9, ADAM-15, and ADAM-17 are upregulated in advanced human atherosclerotic lesions in samples from carotid, aortic, and femoral territories compared to samples from internal thoracic artery (ITA) free of atherosclerotic plaques. Western analysis indicated that the majority of these ADAMs were in the catalytically active form. ADAM-9, ADAM-15, and ADAM-17-expressing cells were shown to co-localize with CD68-positive cells of monocytic origin in the atherosclerotic plaques using immunohistochemistry and double-staining immunofluorescence analysis. Co-localization was demonstrated in all vascular territories. In the carotid territory, cells expressing the ADAMs co-distributed also with smooth muscle cells and, in femoral territory, with CD31-positive endothelial cells, indicating that the ADAM expression pattern depends on vascular bed territory. CONCLUSIONS: Present findings provide strong evidence for the involvement of catalytically active ADAM-9, ADAM-15, and ADAM-17 in advanced atherosclerosis, most notably associated with cells of monocytic origin.


Subject(s)
ADAM Proteins/metabolism , Arteries/metabolism , Atherosclerosis/metabolism , Macrophages/metabolism , Membrane Proteins/metabolism , ADAM17 Protein , Aged , Aged, 80 and over , Atherosclerosis/immunology , Disease Progression , Female , Gene Expression Profiling , Humans , Male , Middle Aged , Oligonucleotide Array Sequence Analysis , RNA, Messenger/metabolism , Up-Regulation
5.
BMC Mol Biol ; 8: 90, 2007 Oct 15.
Article in English | MEDLINE | ID: mdl-17937806

ABSTRACT

BACKGROUND: ADAM15 is a metalloprotease-disintegrin implicated in ectodomain shedding and cell adhesion. Aberrant ADAM15 expression has been associated with human cancer and other disorders. We have previously shown that the alternative splicing of ADAM15 transcripts is mis-regulated in cancer cells. To gain a better understanding of ADAM15 regulation, its genomic organization and regulatory elements as well as the alternative exon use in human tissues were characterized. RESULTS: Human ADAM15, flanked by the FLJ32785/DCST1 and ephrin-A4 genes, spans 11.4 kb from the translation initiation codon to the polyadenylation signal, being the shortest multiple-exon ADAM gene. The gene contains 23 exons varying from 63 to 316 bp and 22 introns from 79 to 1283 bp. The gene appeared to have several transcription start sites and their location suggested the promoter location within a CpG island proximal to the translation start. Reporter expression experiments confirmed the location of functional GC-rich, TATAless and CAATless promoter, with the most critical transcription-supporting elements located -266 to -23 bp relative to the translation start. Normal human tissues showed different complex patterns of at least 13 different ADAM15 splice variants arising from the alternative use of the cytosolic-encoding exons 19, 20a/b, and 21a/b. The deduced ADAM15 protein isoforms have different combinations of cytosolic regulatory protein interaction motifs. CONCLUSION: Characterization of human ADAM15 gene and identification of elements involved in the regulation of transcription and alternative splicing provide important clues for elucidation of physiological and pathological roles of ADAM15. The present results also show that the alternative exon use is a physiological post-transcriptional mechanism regulating ADAM15 expression in human tissues.


Subject(s)
ADAM Proteins/genetics , Alternative Splicing/physiology , Exons/physiology , Gene Expression Regulation, Enzymologic/physiology , Membrane Proteins/genetics , ADAM Proteins/biosynthesis , Amino Acid Motifs/genetics , Cell Adhesion/physiology , Cell Line , Codon, Initiator/physiology , CpG Islands/physiology , Ephrin-A4/genetics , Ephrin-A4/metabolism , Humans , Membrane Proteins/biosynthesis , Neoplasms/enzymology , Neoplasms/genetics , Organ Specificity/physiology , Promoter Regions, Genetic/physiology , Protein Isoforms/biosynthesis , Protein Isoforms/genetics
6.
Trends Biochem Sci ; 30(7): 413-22, 2005 Jul.
Article in English | MEDLINE | ID: mdl-15949939

ABSTRACT

ADAM metalloproteinase disintegrins have emerged as the major proteinase family that mediates ectodomain shedding, the proteolytic release of extracellular domains from their membrane-bound precursors. Recent gene-manipulation studies have established the role of ADAM-mediated shedding in mammalian physiology and, in addition, raised the issue of functional redundancy among ADAM sheddases. ADAM sheddases activate, for example, growth factors and cytokines, thus regulating signalling pathways that are important in development and pathological processes such as cancer. The recent studies have also begun to elucidate the substrate specificity and the mechanisms that control ADAM-mediated shedding events that regulate, for example, growth-factor and Notch signalling, and the processing of the amyloid precursor protein.


Subject(s)
Metalloendopeptidases , Amyloid beta-Protein Precursor/metabolism , Animals , Humans , Membrane Proteins/metabolism , Metalloendopeptidases/genetics , Metalloendopeptidases/physiology , Mitogen-Activated Protein Kinases/metabolism , Receptors, Notch , Signal Transduction/physiology
7.
Genes Chromosomes Cancer ; 41(4): 366-78, 2004 Dec.
Article in English | MEDLINE | ID: mdl-15384173

ABSTRACT

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.


Subject(s)
Breast Neoplasms/genetics , Disintegrins/genetics , Gene Dosage , Membrane Proteins/genetics , Metalloendopeptidases/genetics , ADAM Proteins , Alternative Splicing , Breast Neoplasms/metabolism , Cell Line, Tumor , Cluster Analysis , Disintegrins/biosynthesis , Exons , Female , Humans , In Situ Hybridization , Membrane Proteins/biosynthesis , Metalloendopeptidases/biosynthesis , RNA, Messenger/biosynthesis
SELECTION OF CITATIONS
SEARCH DETAIL
...