Disease relevance of ADAMTS1

• METHODS: Expression of ADAMTS1 in human retinal endothelial cells (HRECs), human umbilical vein endothelial cells (HUVECs), and the mouse model of ischemia-induced retinal neovascularization was assayed by real-time PCR and Western blot analysis [1].
• Our studies show that seven of the ADAMTS genes (ADAMTS1, 3, 5, 8, 9, 10, and 18) are consistently down-regulated in breast carcinomas with respect to nonneoplastic mammary tissue, irrespective of the heterogeneity of the samples and the tumor type or grade (Mann-Whitney U test, P < 0.0001 for each gene) [2].
• A hallmark of rheumatoid- and osteoarthritis (OA) is proinflammatory cytokine-induced degeneration of cartilage collagen and aggrecan by matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS) [3].
• The expression of ADAMTS genes in ARPE-19 cells and the transcriptional stimulation of some family members by TNFalpha may implicate them in inflammatory eye disease and the compromise of retinal matrix structure, which is evident in age-related macular degeneration (ARMD) and other retinal pathologies [4].
• Background: ADAMTS1 and ADAMTS8 are proteases involved in extracellular matrix proteolysis and antiangiogenesis, but little is known about their expression and function in cerebral ischemia [5].
• In the promoter region of ADAMTS1, we found at least three putative hypoxia-inducible factor (HIF) binding sites, and the chromatin immunoprecipitation assay revealed HIF-1 binding to HIF binding sites in the promoter region of ADAMTS1 under hypoxia [6].

Psychiatry related information on ADAMTS1

• Metalloproteinase ADAMTS-1 but not ADAMTS-5 is manifold overexpressed in neurodegenerative disorders as Down syndrome, Alzheimer's and Pick's disease [7].
• Methamphetamine [METH ("speed")] is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans [8].
• Intensity of meth use and sexual risk behavior were significantly correlated [9].
• The 1 mol-eq anti-METH mAb dose significantly reduced the duration of METH-induced locomotor activity (horizontal locomotion and rearing events), heart rate and blood pressure effects from 2 to 3 h to about an hour [10].
• Lasting alterations in social behaviour, anxiety, depressive symptoms and memory have been demonstrated in laboratory rats given MDMA or METH and this matches long-term changes reported in some human studies [11].

High impact information on ADAMTS1

• Treatment of methylcholanthrene-induced (Meth A) ascites tumors with IL-2 and > or =3 mg per kg body weight M40403 induced 50% complete remissions lasting for more than 200 d, which was longer than those of untreated mice (15-d median survival) or mice treated with IL-2 alone (22-d median) [12].
• A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13) [13].
• Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura [13].
• Targeted disruption of the mouse ADAMTS-1 gene resulted in growth retardation with adipose tissue malformation [14].
• Furthermore, ADAMTS-1(-/-) mice demonstrated enlarged renal calices with fibrotic changes from the ureteropelvic junction through the ureter, and abnormal adrenal medullary architecture without capillary formation [14].

Chemical compound and disease context of ADAMTS1

• Catechin gallate esters therefore provide selective inhibition of certain members of the ADAMTS group of enzymes and could constitute an important nutritional aid in the prevention of arthritis as well as being part of an effective therapy in the treatment of joint disease and other pathologies involving the action of these enzymes [15].
• Chemical modification of recombinant interleukin 2 by polyethylene glycol increases its potency in the murine Meth A sarcoma model [16].
• The transplantable murine fibrosarcoma, Meth A, a TNF-sensitive line in vivo, was less sensitive to rhTNF and host toxicity was reduced when the hosts were pretreated with uric acid, a major reactive oxygen scavenger in humans and certain other primates [17].
• The antitumor effects of recombinant human tumor necrosis factor-alpha (rTNF-alpha) and 5-fluorouracil (5-FU) in combination treatment were examined on Meth A fibrosarcoma implanted intradermally in mice [18].
• Homologous series of L-methionine alkyl ester hydrochlorides and tosylates were synthesized and evaluated for in vitro growth inhibitory activity in Meth A sarcoma [19].

Biological context of ADAMTS1

• In the present study, we demonstrate that ADAMTS1 significantly blocks VEGFR2 phosphorylation with consequent suppression of endothelial cell proliferation [20].
• We identified a subgroup of ADAMTSs, based on functional and amino acid sequence similarity (ADAMTS1, 4, 5, 8 and 15), to be the focus of further study in breast carcinoma [21].
• In addition, the potential function of endothelial cell-derived ADAMTS1 on cell proliferation was investigated [1].
• Therefore, VEGF upregulation of ADAMTS1, a potent angiogenesis inhibitor, may represent a mechanism for feedback inhibition of angiogenesis and retinal neovascularization [1].
• Evaluation of ADAMTS1 catalytic activity on a panel of extracellular matrix proteins showed a restrictive substrate specificity which includes some proteoglycans [22].

Anatomical context of ADAMTS1

• ADAMTS1, 2, 7, 8, 10, and 12 are expressed predominantly in stromal fibroblasts [2].
• In human chondrocytes, OSM+TNFalpha also enhanced ADAMTS-1 and -4 expression, but not that of other ADAMTSs [23].
• METHODS: The effect of TGFbeta on mRNA expression in prostatic stromal cells was determined by real-time qRT-PCR using primers to ADAMTS-1, -4, -5, -9, -15, versican, and TIMP-3 [24].
• Expression of ADAMTS metalloproteinases in the retinal pigment epithelium derived cell line ARPE-19: transcriptional regulation by TNFalpha [4].
• Differential expression of genes coding for EGF-like factors and ADAMTS1 following gonadotropin stimulation in normal and transformed human granulosa cells [25].

Associations of ADAMTS1 with chemical compounds

• The interaction required the heparin-binding domain of the growth factor, because VEGF121 failed to bind to ADAMTS1 [20].
• The effect of ADAMTS1 on endothelial cell proliferation was evaluated using siRNA knockdown and [3H] thymidine incorporation [1].
• VEGF upregulation of ADAMTS1 expression was completely abolished by the inhibition of protein kinase C by calphostin C and largely blocked by the specific inhibition of PKCbeta [1].
• VWFCP consists of 1427 amino acid residues and has a signal peptide, a short propeptide terminating in the sequence RQRR, a reprolysin-like metalloprotease domain, a disintegrin-like domain, a thrombospondin-1 repeat, a Cys-rich domain, an ADAMTS spacer, seven additional thrombospondin-1 repeats, and two CUB domains [26].
• High-density lipoprotein subfraction 3 decreases ADAMTS-1 expression induced by lipopolysaccharide and tumor necrosis factor-alpha in human endothelial cells [27].

Physical interactions of ADAMTS1

• The ability of ADAMTS1 to bind VEGF and functionally inactivate VEGFR2 is reversible as dissociation of the complex results in active growth factor [28].

Enzymatic interactions of ADAMTS1

• We conclude that versican V1 proteolysis in vivo can be catalyzed by one or more members of the ADAMTS family of metalloproteinases [29].

Regulatory relationships of ADAMTS1

• CONCLUSIONS: These results indicate that VEGF significantly induces ADAMTS1 expression in endothelial cells in a PKC-dependent fashion [1].
• In vivo, the application of wortmannin promoted the formation of TNF-induced hemorrhages and intratumoral necroses in murine meth A tumors [30].
• This study aims to identify other metalloproteinase genes of the ADAM (A Disintegin And Metalloproteinase) and ADAMTS families that are regulated by PPAR gamma or RXR agonists, which are potentially important in type 2 diabetes and/or related atherosclerosis [31].
• A species at 115 kDa and some other protein bands began with F(236)VSSHRYV(243), indicating that METH-1 proenzyme might be activated by a proprotein convertase such as furin by cleaving the R(235)-F(236) peptide bond [32].
• Moreover, the concentration needed for total inhibition of these members of the ADAMTS group is approximately two orders of magnitude lower than that which is needed to partially inhibit collagenase or ADAM-10 activity [15].

Other interactions of ADAMTS1

• CONCLUSION: This is the first comprehensive expression profile of all known MMP, ADAMTS, and TIMP genes in cartilage [33].
• CONCLUSIONS: OSM+TNFalpha up regulates membrane associated aggrecanase activity and several ADAMTS aggrecanase mRNAs in chondrocytes [23].
• A sub-group of the ADAMTS lineage of metalloproteases possess versican-degrading properties and are potential regulators of proteoglycan accumulation associated with BPH [24].
• Oncostatin M in combination with tumour necrosis factor {alpha} induces a chondrocyte membrane associated aggrecanase that is distinct from ADAMTS aggrecanase-1 or -2 [23].
• The adamalysin-thrombospondin (ADAMTS) proteinases are a relatively newly described branch of the metzincin family that contain metalloproteinase, disintegrin, and thrombospondin motifs [2].

Analytical, diagnostic and therapeutic context of ADAMTS1

• A second activity of ADAMTS1 requires the catalytic domain as a single point mutation in the metalloproteinase domain renders the protein inactive in tumor xenograft assays [28].
• Expression analysis was undertaken using a combination of reverse transcription polymerase chain reaction (RT-PCR) and Northern blotting experiments, which together detected the expression of mRNAs for several ADAMTS proteins, all of which have active site motifs characteristic of matrix metalloproteases (MMPs) [4].
• Methods: Male Sprague-Dawley rats were subjected to pMCAO, and ischemic penumbra was collected at 2, 24 h, 3, 7, and 21 days after inducing ischemia, ADAMTS1, ADAMTS8, and the four housekeeping genes were quantified using real-time polymerase chain reaction (PCR) [5].
• Frontal cortex of controls, DS, AD and PD were homogenized and extracted proteins were used for immunoblotting using antibodies against ADAMTS-1 and ADAMTS-5 [7].
• To elucidate the biological role of ADAMTS-1, we developed ADAMTS-1-null mice by gene targeting [14].

References