We have previously identified 67 exons on a yeast artificial chromosome contig spanning 1.5 Mb around the multidrug resistance 1 gene region of human chromosome 7q21.1. In this study, we identified three novel cytoplasmic variants (MDC2-gamma, MDC2-delta, and MDC2-epsilon) of the human metalloprotease-like disintegrin-like cysteine-rich protein 2 (MDC2) among these exons by screening a human brain cDNA library and also by using a reverse transcription polymerase chain reaction. Genomic sequence analysis strongly supported the idea that the variations in the cytoplasmic domain were generated by alternative splicing. The expression of MDC2 variant forms in human brain tissue and gliomas was examined by reverse transcription polymerase chain reaction and RNase protection assay. MDC2-epsilon was expressed only in the cortical and hippocampal regions in human brain, but not in gliomas. In contrast, MDC2-gamma was a major form expressed in human gliomas. Specific expression of these cytoplasmic variants of MDC2 in human brain and its malignancies is discussed.
"ADAM-19, as well as many others such as ADAM-8, -9, -12, 15 and -17 expressed in human malignant tumors, is involved in the regulation of growth factor activities and integrin functions, leading to the promotion of cell growth and invasion . ADAM-22 (MDC2) is expressed in normal brain and some low-grade gliomas, but not in high-grade gliomas . In vitro, ADAM-22 inhibits cellular proliferation of glioma derived astrocytes. "
[Show abstract][Hide abstract] ABSTRACT: The A Disintegrin And Metalloprotease (ADAM) proteins belong to the metzincin-superfamily of Zn-dependent metalloproteinases that shed the extracellular domains of membrane-bound growth factors, cytokines and their receptors. The latter play a central role in cell signaling and contribute a potential target in cancer therapy. Of particular interest are the ErBB/HER family of growth factor receptors associated with elevated intrinsic tyrosine kinase activity. Overexpression of ADAMs and cell signaling components have also been implicated in the development and progression of a variety of tumor types. Emerging evidence has suggested that the ADAM proteins are involved in tumour cell proliferation, in angiogenesis as well as metastasis. Therefore, strategies targeting ADAMs may constitute an important target for the design of cancer drugs. The review will focus on current understanding of the role of ADAM in the physiological and pathological functions associated with cancer. It is the intention of the review to provide insights which may assist in the development of ADAM-based approaches for the treatment of human cancers.
Current cancer drug targets 01/2009; 8(8):720-32. DOI:10.2174/156800908786733478 · 3.52 Impact Factor
"In the case of human ADAM22, isolation of five splicing variants and existence of two terminating exons have been reported [13,20,21]. However, the latter terminating exon (exon 31) of the mouse species has not been identified yet. "
[Show abstract][Hide abstract] ABSTRACT: ADAM22 is a member of the ADAM gene family, but the fact that it is expressed only in the nervous systems makes it unique. ADAM22's sequence similarity to other ADAMs suggests it to be an integrin binder and thus to have a role in cell-cell or cell-matrix interactions. To elucidate the physiological functions of ADAM22, we employed gene targeting to generate ADAM22 knockout mice.
ADAM22-deficient mice were produced in a good accordance with the Mendelian ratio and appeared normal at birth. After one week, severe ataxia was observed, and all homozygotes died before weaning, probably due to convulsions. No major histological abnormalities were detected in the cerebral cortex or cerebellum of the homozygous mutants; however, marked hypomyelination of the peripheral nerves was observed.
The results of our study demonstrate that ADAM22 is closely involved in the correct functioning of the nervous system. Further analysis of ADAM22 will provide clues to understanding the mechanisms of human diseases such as epileptic seizures and peripheral neuropathy.
"Yagami-Hiromasa et al. 1995; 9 Harris et al. 1997; 10 Gilpin et al. 1998; 11 Kratzschmar et al. 1996; 12 Patel et al. 1998; 13 Frayne et al. 2002; 14 Kurisaki et al. 1998; 15 Poindexter et al. 1999; 16 Harada et al. 2000; 17 Cal et al. 2000; 18 Roberts et al. 1999; 19 Howard et al. 2000; 20 Howard et al. 2001; 21 Cerretti et al. 1999; 22 Xu et al. 1999; 23 Yoshinaka et al. 2002 MP active refers to either predicted (p) or already demonstrated (d) activity based on the amino acid sequence of the catalytic active site in metalloprotease domain ADAM12 is a member of ADAMs family, which has been implicated in cell adhesion, cell fusion and fusion signalling (Wolfsberg et al. 1995). ADAM12 comprises a pro-domain, a metalloprotease domain, a disintegrin domain, a cystein-rich domain, an epidermal growth factor (EGF)-like domain, and a transmembrane domain with an attached cytoplasmic tail. "
[Show abstract][Hide abstract] ABSTRACT: Total hip replacement is the golden standard treatment for severe osteoarthritis refractory for conservative treatment. Aseptic loosening and osteolysis are the major long-term complications after total hip replacement. Foreign body giant cells and osteoclasts are locally formed around aseptically loosening implants from precursor cells by cell fusion. When the foreign body response is fully developed, it mediates inflammatory and destructive host responses, such as collagen degradation. In the present study, it was hypothesized that the wear debris and foreign body inflammation are the forces driving local osteoclast formation, peri-implant bone resorption and enhanced tissue remodeling. Therefore the object was to characterize the eventual expression and the role of fusion molecules, ADAMs (an abbreviation for A Disintegrin And Metalloproteinase, ADAM9 and ADAM12) in the fusion of progenitor cells into multinuclear giant cells. For generation of such cells, activated macrophages trying to respond to foreign debris play an important role. Matured osteoclasts together with activated macrophages mediate bone destruction by secreting protons and proteinases, including matrix metalloproteinases (MMPs) and cathepsin K. Thus this study also assessed collagen degradation and its relationship to some of the key collagenolytic proteinases in the aggressive synovial membrane-like interface tissue around aseptically loosened hip replacement implants. ADAMs were found in the interface tissues of revision total hip replacement patients. Increased expression of ADAMs at both transcriptional and translational levels was found in synovial membrane-like interface tissue of revision total hip replacement (THR) samples compared with that in primary THR samples. These studies also demonstrate that multinucleate cell formation from monocytes by stimulation with macrophage-colony stimiulating factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL) is characterized by time dependent changes of the proportion of ADAMs positive cells. This was observed both in the interface membrane in patients and in two different in vitro models. In addition to an already established MCS-F and RANKL driven model, a new virally (parainfluenza 2) driven model (of human salivary adenocarcinoma (HSY) cells or green monkey kidney (GMK) cells) was developed to study various fusion molecules and their role in cell fusion in general. In interface membranes, collagen was highly degraded and collagen degradation significantly correlated with the number of local cells containing collagenolytic enzymes, particularly cathepsin K. As a conclusion, fusion molecules ADAM9 and ADAM12 seem to be dynamically involved in cell-cell fusion processes and multinucleate cell formation. The highly significant correlation between collagen degradation and collagenolytic enzymes, particularly cathepsin K, indicates that the local acidity of the interface membrane in the pathologic bone and soft tissue destruction. This study provides profound knowledge about cell fusion and mechanism responsible for aseptic loosening as well as increases knowledge helpful for prevention and treatment. The formation of multinucleated cells such as myotubes, macrophage-derived giant cells and osteoclasts is the result of cell-cell fusion of mononuclear precursors. The ADAMs (an acronym for A Disintegrin And Metalloproteinase) is a family of multifunctional proteins that exhibit a significant similarity with snake venom metalloproteases and are involved in cell-cell fusion processes. As fusion molecules, ADAM12 and ADAM9 are involved in cell-cell fusion processes and participate in myoblast fusion and, also in osteoclast fusion. The aims of the proposed project are to characterize ADAMs expression and regulations both in the interface membrane of total hip replacement in the patients and in in vitro cell model. Further study of the relationship between the structure and function of ADAMs may provide profound knowledge of its role in cell fusion, and even one attractive therapeutic target.
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