Genomes and Genes
Gene Symbol: TIMP-3
Description: TIMP metallopeptidase inhibitor 3
Alias: HSMRK222, K222, K222TA2, SFD, metalloproteinase inhibitor 3, MIG-5 protein, TIMP-3, protein MIG-5, tissue inhibitor of metalloproteinases 3
- van der Velden P, Zuidervaart W, Hurks M, Pavey S, Ksander B, Krijgsman E, et al. Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development. Int J Cancer. 2003;106:472-9 pubmed..We demonstrate in the cell lines that TIMP3 expression is regulated by methylation. These observations were confirmed in primary uveal melanoma and suggests a role for TIMP3 in uveal melanoma development. ..
- Yeow K, Kishnani N, Hutton M, Hawkes S, Murphy G, Edwards D. Sorsby's fundus dystrophy tissue inhibitor of metalloproteinases-3 (TIMP-3) mutants have unimpaired matrix metalloproteinase inhibitory activities, but affect cell adhesion to the extracellular matrix. Matrix Biol. 2002;21:75-88 pubmed..Mutations in the TIMP3 gene have been linked to Sorsby's fundus dystrophy (SFD), an autosomal dominant inherited retinal degenerative disease that leads to blindness...
- Das A, Seynhaeve A, Rens J, Vermeulen C, Koning G, Eggermont A, et al. Differential TIMP3 expression affects tumor progression and angiogenesis in melanomas through regulation of directionally persistent endothelial cell migration. Angiogenesis. 2014;17:163-77 pubmed publisher..Taken together, our results demonstrate that TIMP3 expression correlates with inhibition of directionally persistent EC migration and adversely affects the angiogenic potential and growth of melanomas. ..
- Langton K, McKie N, Smith B, Brown N, Barker M. Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells. Hum Mol Genet. 2005;14:3579-86 pubmedSorsby's fundus dystrophy (SFD) is an autosomal dominant degenerative disease of the retina, caused by mutations in exon 5 of the gene for tissue inhibitor of metalloproteinases-3 (TIMP-3)...
- Iseri O, Kars M, Arpaci F, Gunduz U. Gene expression analysis of drug-resistant MCF-7 cells: implications for relation to extracellular matrix proteins. Cancer Chemother Pharmacol. 2010;65:447-55 pubmed publisher..Correlation of each specific ECM component with drug resistance requires further analysis. ..
- Qureshi H, Ricci G, Zafarullah M. Smad signaling pathway is a pivotal component of tissue inhibitor of metalloproteinases-3 regulation by transforming growth factor beta in human chondrocytes. Biochim Biophys Acta. 2008;1783:1605-12 pubmed publisher..These results suggest that receptor-activated Smad2 and Smad3 and co-Smad4 critically mediate TGF-beta-stimulated TIMP-3 expression in human chondrocytes and TIMP-3 gene is a target of Smad signaling pathway. ..
- Neale B, Fagerness J, Reynolds R, Sobrin L, Parker M, Raychaudhuri S, et al. Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC). Proc Natl Acad Sci U S A. 2010;107:7395-400 pubmed publisher..Results implicate different biologic pathways than previously reported and provide new avenues for prevention and treatment of AMD. ..
- Byrne J, Tomasetto C, Rouyer N, Bellocq J, Rio M, Basset P. The tissue inhibitor of metalloproteinases-3 gene in breast carcinoma: identification of multiple polyadenylation sites and a stromal pattern of expression. Mol Med. 1995;1:418-27 pubmed..The strong expression of the TIMP3 gene by fibroblastic cells in breast carcinoma supports the importance of tumor stroma as a source of factors influencing human carcinoma growth and progression. ..
- Nayak C, Carvalho A, Jeronimo C, Henrique R, Kim M, Hoque M, et al. Positive correlation of tissue inhibitor of metalloproteinase-3 and death-associated protein kinase hypermethylation in head and neck squamous cell carcinoma. Laryngoscope. 2007;117:1376-80 pubmed..TIMP-3 promoter hypermethylation is elevated in HNSCC and is highly correlated with DAPK hypermethylation, implying a functional relationship between these genes. ..
- Barbazetto I, Hayashi M, Klais C, Yannuzzi L, Allikmets R. A novel TIMP3 mutation associated with Sorsby fundus dystrophy. Arch Ophthalmol. 2005;123:542-3 pubmed
- Kang K, Park S, Rho S, Lee J. Tissue inhibitor of metalloproteinases-3 interacts with angiotensin II type 2 receptor and additively inhibits angiogenesis. Cardiovasc Res. 2008;79:150-60 pubmed publisher..These combined results suggest that two angiostatic molecules may have an important biological role in regulating potent anti-angiogenic effects and possibly may have a role in anti-tumour therapy. ..
- Selaru F, Olaru A, Kan T, David S, Cheng Y, Mori Y, et al. MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. Hepatology. 2009;49:1595-601 pubmed publisher..995. Inhibitors of miR-21 increased protein levels of programmed cell death 4 (PDCD4) and tissue inhibitor of metalloproteinases 3 (TIMP3). Notably, messenger RNA levels of TIMP3 were significantly lower in CCAs than in normals...
- Röhrs S, Dirks W, Meyer C, Marschalek R, Scherr M, Slany R, et al. Hypomethylation and expression of BEX2, IGSF4 and TIMP3 indicative of MLL translocations in acute myeloid leukemia. Mol Cancer. 2009;8:86 pubmed publisher..These results suggest that the conspicuous expression of the TSG BEX2, IGSF4 and TIMP3 in MLLmu AML cell lines is the consequence of altered epigenetic properties of MLL fusion proteins. ..
- Qi J, Ebrahem Q, Yeow K, Edwards D, Fox P, Anand Apte B. Expression of Sorsby's fundus dystrophy mutations in human retinal pigment epithelial cells reduces matrix metalloproteinase inhibition and may promote angiogenesis. J Biol Chem. 2002;277:13394-400 pubmedSorsby's fundus dystrophy (SFD) is an autosomal dominant degenerative disease of the macula caused by mutations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) gene...
- Wisniewska M, Goettig P, Maskos K, Belouski E, Winters D, Hecht R, et al. Structural determinants of the ADAM inhibition by TIMP-3: crystal structure of the TACE-N-TIMP-3 complex. J Mol Biol. 2008;381:1307-19 pubmed publisherTIMP-3 (tissue inhibitor of metalloproteinases 3) is unique among the TIMP inhibitors, in that it effectively inhibits the TNF-alpha converting enzyme (TACE)...
- Xu C, Hou Z, Zhan P, Zhao W, Chang C, Zou J, et al. EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer. Med Oncol. 2013;30:713 pubmed publisher..Taken together, our findings indicate that EZH2 accelerates cancer cell migration, in part, via the repression of TIMP-3 expression, suggesting a potential mechanism by which EZH2 promotes lung cancer progression and metastasis. ..
- Jacobson S, Cideciyan A, Regunath G, Rodriguez F, Vandenburgh K, Sheffield V, et al. Night blindness in Sorsby's fundus dystrophy reversed by vitamin A. Nat Genet. 1995;11:27-32 pubmedSorsby's fundus dystrophy (SFD) is an autosomal dominant retinal degeneration caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. Mechanisms of the visual loss in SFD, however, remain unknown...
- Li Z, Clarke M, Barker M, McKie N. TIMP3 mutation in Sorsby's fundus dystrophy: molecular insights. Expert Rev Mol Med. 2005;7:1-15 pubmed..a role, SFD has been shown to be a single-gene disorder, linked to mutations in exon 5 of the tissue inhibitor of metalloproteinases 3 (TIMP3) gene on chromosome 22q12-q13...
- Langton K, McKie N, Curtis A, Goodship J, Bond P, Barker M, et al. A novel tissue inhibitor of metalloproteinases-3 mutation reveals a common molecular phenotype in Sorsby's fundus dystrophy. J Biol Chem. 2000;275:27027-31 pubmedSorsby's fundus dystrophy (SFD) is a dominantly inherited degenerative disease of the retina that leads to loss of vision in middle age...
- Barth J, Yu Y, Song W, Lu K, Dashti A, Huang Y, et al. Oxidised, glycated LDL selectively influences tissue inhibitor of metalloproteinase-3 gene expression and protein production in human retinal capillary pericytes. Diabetologia. 2007;50:2200-8 pubmed..Among the genes encoding for MMPs and TIMPs expressed in retinal pericytes, TIMP3 is uniquely regulated by HOG-LDL. Reduced TIMP3 expression might contribute to microvascular abnormalities in diabetic retinopathy. ..
- Song B, Wang C, Liu J, Wang X, Lv L, Wei L, et al. MicroRNA-21 regulates breast cancer invasion partly by targeting tissue inhibitor of metalloproteinase 3 expression. J Exp Clin Cancer Res. 2010;29:29 pubmed publisher..As knockdown of miR-21 increased TIMP3 protein expression and luciferase reporter activity, our data suggests that miR-21 could promote invasion in breast cancer cells via its regulation of TIMP3. ..
- Garofalo M, Di Leva G, Romano G, Nuovo G, Suh S, Ngankeu A, et al. miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell. 2009;16:498-509 pubmed publisher..Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation through the c-Jun transcription factor. ..
- Kornfeld J, Meder S, Wohlberg M, Friedrich R, Rau T, Riethdorf L, et al. Overexpression of TACE and TIMP3 mRNA in head and neck cancer: association with tumour development and progression. Br J Cancer. 2011;104:138-45 pubmed publisher..TACE-dependent proteolysis is regulated by its inhibitor, tissue inhibitor of metalloproteinases 3 (TIMP3)...
- Chen W, Stambolian D, Edwards A, Branham K, Othman M, Jakobsdottir J, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A. 2010;107:7401-6 pubmed publisher..Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies. ..
- Darnton S, Hardie L, Muc R, Wild C, Casson A. Tissue inhibitor of metalloproteinase-3 (TIMP-3) gene is methylated in the development of esophageal adenocarcinoma: loss of expression correlates with poor prognosis. Int J Cancer. 2005;115:351-8 pubmed..These studies have demonstrated association between methylation of the TIMP-3 gene and BE and EADC. Reduced expression of TIMP-3 protein in EADC is associated with increased tumour invasiveness and reduced patient survival. ..
- Ninomiya I, Kawakami K, Fushida S, Fujimura T, Funaki H, Takamura H, et al. Quantitative detection of TIMP-3 promoter hypermethylation and its prognostic significance in esophageal squamous cell carcinoma. Oncol Rep. 2008;20:1489-95 pubmed..0357). These results demonstrate that TIMP-3 hypermethylation is associated with lower TIMP-3 protein expression in ESCC and with poor patient survival due to a high frequency of recurrence by pleural dissemination. ..
- Wang N, Zhang C, He J, Duan X, Wang Y, Ji X, et al. MiR-21 down-regulation suppresses cell growth, invasion and induces cell apoptosis by targeting FASL, TIMP3, and RECK genes in esophageal carcinoma. Dig Dis Sci. 2013;58:1863-70 pubmed publisher..FASL, TIMP3 and RECK are direct targets of miR-21. miR-21 down-regulation inhibits cell growth, invasion and induces cells to apoptosis by targeting FASL, TIMP3 and RECK genes. ..
- Turner S, Mangnall D, Bird N, Bunning R, Blair Zajdel M. Expression of ADAMTS-1, ADAMTS-4, ADAMTS-5 and TIMP3 by hepatocellular carcinoma cell lines. Int J Oncol. 2012;41:1043-9 pubmed publisher..The pro-inflammatory cytokines IL-1?, TNF-? or IL-6 induced changes in mRNA expression, although these did not translate to the protein level. ..
- Sun W, Zaboli D, Wang H, Liu Y, Arnaoutakis D, Khan T, et al. Detection of TIMP3 promoter hypermethylation in salivary rinse as an independent predictor of local recurrence-free survival in head and neck cancer. Clin Cancer Res. 2012;18:1082-91 pubmed publisher..Detection of promoter hypermethylation of TIMP3 in pretreatment salivary rinse is independently associated with local recurrence-free survival in patients with HNSCC and may be a valuable salivary rinse biomarker for HNSCC recurrence. ..
- Zhang H, Wang Y, Han G, Shi Y. TIMP-3 gene transfection suppresses invasive and metastatic capacity of human hepatocarcinoma cell line HCC-7721. Hepatobiliary Pancreat Dis Int. 2007;6:487-91 pubmed..The results suggest that upregulation of TIMP-3 expression in HCC-7721 cells inhibits invasion capacity in vitro as well as tumorigenic and metastatic potential in nude mice. ..
- Cardellini M, Menghini R, Martelli E, Casagrande V, Marino A, Rizza S, et al. TIMP3 is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SirT1. Diabetes. 2009;58:2396-401 pubmed publisher..Studies in vascular cells confirmed the role of SirT1 in tuning TIMP3 expression. ..
- Langton K, Barker M, McKie N. Localization of the functional domains of human tissue inhibitor of metalloproteinases-3 and the effects of a Sorsby's fundus dystrophy mutation. J Biol Chem. 1998;273:16778-81 pubmed..These data favor the hypothesis that the TIMP-3 mutations seen in Sorsby's fundus dystrophy contribute to disease progression by accumulation of mutant protein rather than by the loss of functional TIMP-3. ..
- Bashash M, Shah A, Hislop G, Treml M, Bretherick K, Janoo Gilani R, et al. Genetic polymorphisms at TIMP3 are associated with survival of adenocarcinoma of the gastroesophageal junction. PLoS ONE. 2013;8:e59157 pubmed publisher..TIMP3 genetic variants are associated with survival and may be potentially useful in optimizing treatment strategies for individual patients. ..
- Jacobson S, Cideciyan A, Bennett J, Kingsley R, Sheffield V, Stone E. Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy. Arch Ophthalmol. 2002;120:376-9 pubmed
- Stohr H, Roomp K, Felbor U, Weber B. Genomic organization of the human tissue inhibitor of metalloproteinases-3 (TIMP3). Genome Res. 1995;5:483-7 pubmed..recently, we have shown that mutations in TIMP3 cause the autosomal dominant disorder Sorsby's fundus dystrophy (SFD). This is a macular degeneration disorder with characteristic ECM irregularities in Bruch's membrane...
- Forsius H, Eriksson A, Suvanto E, Alanko H. Pseudoinflammatory fundus dystrophy with autosomal recessive inheritance. Am J Ophthalmol. 1982;94:634-49 pubmed..The affected parents are consanguineous in many ways and each of their eight children is affected. ..
- Lee M, Atkinson S, Murphy G. Identification of the extracellular matrix (ECM) binding motifs of tissue inhibitor of metalloproteinases (TIMP)-3 and effective transfer to TIMP-1. J Biol Chem. 2007;282:6887-98 pubmed..This is the first instance of TIMPs being intentionally rendered soluble or ECM-bound. The ability to prepare TIMPs in soluble or ECM-bound forms also opens new avenues for future TIMP research. ..
- Lin R, Blumenkranz M, Binkley J, Wu K, Vollrath D. A novel His158Arg mutation in TIMP3 causes a late-onset form of Sorsby fundus dystrophy. Am J Ophthalmol. 2006;142:839-48 pubmedTo describe the phenotype and genotype of a family with suspected Sorsby fundus dystrophy (SFD). Case reports and results of deoxyribonucleic acid (DNA) analysis...
- Apte S, Olsen B, Murphy G. The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem. 1995;270:14313-8 pubmed..Instead, differential regulation of the TIMP genes or divergent C-terminal protein sequences may underlie distinct biological functions for each TIMP. ..
- Johnson J, Sala Newby G, Ismail Y, Aguilera C, Newby A. Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages. Arterioscler Thromb Vasc Biol. 2008;28:1647-53 pubmed publisher..These cells are highly invasive and have increased proliferation and apoptosis, all properties expected to destabilise atherosclerotic plaques...
- Kassiri Z, Oudit G, Kandalam V, Awad A, Wang X, Ziou X, et al. Loss of TIMP3 enhances interstitial nephritis and fibrosis. J Am Soc Nephrol. 2009;20:1223-35 pubmed publisher..Taken together, these results provide evidence that TIMP3 is an important mediator of kidney injury, and regulating its activity may have therapeutic benefit for patients with kidney disease...
- Weber B, Vogt G, Pruett R, Stohr H, Felbor U. Mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) in patients with Sorsby's fundus dystrophy. Nat Genet. 1994;8:352-6 pubmed..Among these disorders, Sorsby's fundus dystrophy (SFD), an autosomal dominant condition, provides an excellent mendelian model for the study of the genetically complex ..
- Han X, Zhang H, Jia M, Han G, Jiang W. Expression of TIMP-3 gene by construction of a eukaryotic cell expression vector and its role in reduction of metastasis in a human breast cancer cell line. Cell Mol Immunol. 2004;1:308-10 pubmed..Our experiments further indicated that the potential of metastasis was significantly reduced for the transfected cell line MDA-MB-453. ..
- Armstrong C, Abilleira S, Sitzer M, Markus H, Bevan S. Polymorphisms in MMP family and TIMP genes and carotid artery intima-media thickness. Stroke. 2007;38:2895-9 pubmed..These findings need replication in hypertensive populations to assess their effects more fully. ..
- Anania M, Sensi M, Radaelli E, Miranda C, Vizioli M, Pagliardini S, et al. TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene. 2011;30:3011-23 pubmed publisher..Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC. ..
- Peterson N, Beeghly Fadiel A, Gao Y, Long J, Cai Q, Shu X, et al. Polymorphisms in tissue inhibitors of metalloproteinases-2 and -3 and breast cancer susceptibility and survival. Int J Cancer. 2009;125:844-50 pubmed publisher..Genetic variation in the TIMP-2 and TIMP-3 genes may contribute to individual differences in breast cancer susceptibility and survival. ..
- Karan D, Lin F, Bryan M, Ringel J, Moniaux N, Lin M, et al. Expression of ADAMs (a disintegrin and metalloproteases) and TIMP-3 (tissue inhibitor of metalloproteinase-3) in human prostatic adenocarcinomas. Int J Oncol. 2003;23:1365-71 pubmed..These results suggest that an inverse expression pattern of ADAM-17/TACE and TIMP-3, and the regulation of ADAMs with DHT might play an important role in the pathogenesis of prostate cancer. ..
- Felbor U, Stohr H, Amann T, Schonherr U, Weber B. A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features. Hum Mol Genet. 1995;4:2415-6 pubmed
- Zhe X, Yang Y, Jakkaraju S, Schuger L. Tissue inhibitor of metalloproteinase-3 downregulation in lymphangioleiomyomatosis: potential consequence of abnormal serum response factor expression. Am J Respir Cell Mol Biol. 2003;28:504-11 pubmed..Because timp-3-null mice develop spontaneous emphysema, our findings suggest that SRF-mediated TIMP-3 inhibition might contribute to the tissue damage seen in LAM...
- Capone C, Dabertrand F, Baron Menguy C, Chalaris A, Ghezali L, Domenga Denier V, et al. Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. elife. 2016;5: pubmed publisher..These results support the concept that the balance of TIMP3 and ADAM17 activity modulates CBF through regulation of myocyte KV channel number. ..
- Freour T, Jarry A, Bach Ngohou K, Dejoie T, Bou Hanna C, Denis M, et al. TACE inhibition amplifies TNF-alpha-mediated colonic epithelial barrier disruption. Int J Mol Med. 2009;23:41-8 pubmed..TIMP3 could thus play a major role in inflammatory conditions by creating an autocrine effect leading to amplified epithelial barrier hyperpermeability. ..
- Perera R, Dissanayake P, Senarath U, Wijayaratne L, Karunanayake A, Dissanayake V. Single Nucleotide Variants of Candidate Genes in Aggrecan Metabolic Pathway Are Associated with Lumbar Disc Degeneration and Modic Changes. PLoS ONE. 2017;12:e0169835 pubmed publisher..Predictions of in-silico functional analysis of significant SNVs are inconsistent. ..