Cloning and Characterization of Human Tissue Inhibitor of Metalloproteinases-3

Wilde, Craig G.; Hawkins, Phil R.; Coleman, Roger; Levine, Wendy B.; Delegeane, A M; Okamoto, Penny M.; Ito, Laura Y.; Scott, Randy W.; Seilhamer, Jeffrey J.

doi:10.1089/dna.1994.13.711

Cited by 30 publications

(28 citation statements)

References 25 publications

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“…Three mammalian TIMPs have been characterized at the sequence level: TIMP-1 (20), TIMP-2 (21), and TIMP-3 (22)(23)(24)(25)36). The proteins are classified based on structural similarity to each other as well as their ability to inhibit matrix metalloproteinases.…”

Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Molecular Cloning and Characterization of Human Tissue Inhibitor of Metalloproteinase 4

Greene

Wang

Liu

et al. 1996

Journal of Biological Chemistry

495

300

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The tissue inhibitors of metalloproteinases (TIMPs) constitute a family of proteins, of which three members have so far been described. Using the expressed sequence tag sequencing approach, we have identified a novel TIMP-related cDNA fragment and subsequently cloned a fourth human TIMP (TIMP-4) from a human heart cDNA library. The open reading frame encodes a 224-amino acid precursor including a 29-residue secretion signal. The predicted structure of the new protein shares 37% sequence identity with TIMP-1 and 51% identity with TIMP-2 and -3. The protein has a predicted isoelectric point of 7.34. The open reading frame-directed expression of TIMP-4 protein in MDA-MB-435 human breast cancer cells showed metalloproteinase inhibitory activity on reverse zymography. By Northern analysis, only the adult heart showed abundant TIMP-4 transcripts with a 1.4-kilobase predominant transcript band; very low levels of the transcripts were detected in the kidney, placenta, colon, and testes, and no transcripts were detected in the liver, brain, lung, thymus, and spleen. This unique expression pattern suggests that TIMP-4 may function in a tissue-specific fashion in extracellular matrix homeostasis. Matrix metalloproteinases (MMPs)1 play a critical role in ECM homeostasis. Controlled remodeling of the ECM is an essential aspect in the process of normal development, and deregulated remodeling has been indicated to have a role in the etiology of diseases such as arthritis, periodontal disease, and cancer metastasis (1-5). The overproduction and unrestrained activity of MMPs has been linked to malignant conversion of tumor cells (4 -12). The down-regulation of MMPs may occur at the levels of transcriptional regulation of the genes and activation of secreted proenzymes and through interaction with specific inhibitor proteins such as TIMPs. TIMPs are secreted multifunctional proteins that play pivotal roles in the regulation of ECM metabolism. Their most widely recognized action is as inhibitors of matrix MMPs. Thus, the net MMP activity in the ECM is the result of the balance between activated enzyme levels and TIMPs levels. Augmented MMP activity is associated with the metastatic phenotype of carcinomas, especially breast cancer (7-9, 13-16); the decreased production of TIMP could also result in greater effective enzyme activity and invasive potentials (17-19). These results suggest that an increase in the amount of TIMPs relative to MMPs could function to block tumor cell invasion and metastasis. In fact, tumor cell invasion and metastasis can be inhibited by up-regulation of TIMP expression or by an exogenous supply of TIMPs (17, 40 -44).Three mammalian TIMPs have been characterized at the sequence level: TIMP-1 (20), TIMP-2 (21), and 36). The proteins are classified based on structural similarity to each other as well as their ability to inhibit matrix metalloproteinases. There have been other reports of inhibitors of metalloproteases (IMPs) with characteristics different from these known TIMPs. In some cases these activitie...

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Section: Matrix Metalloproteinases (Mmps)mentioning

confidence: 99%

Molecular Cloning and Characterization of Human Tissue Inhibitor of Metalloproteinase 4

Greene

Wang

Liu

et al. 1996

Journal of Biological Chemistry

495

300

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“…Finally, we have been able to demonstrate that synovial fibroblasts can express TIMP-3 mRNA. TIMP-3 was first isolated in chicken (Ch-imp-3) (6) and then in humans (2,8,10,52,53). Like TIMP-1 and -2, TIMP-3 inhibits MMP activity (6) and stimulates the division of serum-deprived cells (54).…”

Section: Il-6 and Its Soluble Receptormentioning

confidence: 99%

“…So far, the sequences coding for four human TIMPs (TIMP-1, -2, and -3 and, more recently, TIMP-4) have been identified (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The expression of TIMP-1 proved to be both constitutive and inducible, whereas TIMP-2 appeared to be widely expressed but not inducible (1,12).…”

mentioning

confidence: 99%

Interleukin (IL)-6 and Its Soluble Receptor Induce TIMP-1 Expression in Synoviocytes and Chondrocytes, and Block IL-1-induced Collagenolytic Activity

Silacci¹,

Dayer²,

Desgeorges³

et al. 1998

Journal of Biological Chemistry

100

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To define the potential role of interleukin-6 (IL-6) and its soluble receptor ␣ in cartilage metabolism, we analyzed their effects on tissue inhibitor of metalloproteases (TIMP) synthesis by synoviocytes and chondrocytes. TIMP-1 production by isolated human articular synovial fibroblasts and chondrocytes, stimulated by IL-6 and/or its soluble receptor, was first assayed by specific enzyme-linked immunosorbent assay; the slight stimulatory effect of IL-6 on TIMP-1 production by both types of cells was markedly amplified by the addition of soluble receptor, the maximal secretion being observed only at 96 h. TIMP-1 mRNA expression, determined by ribonuclease protection assay, was induced by IL-6 together with its soluble receptor, but TIMP-2 and -3 mRNAs were not affected by these factors. A specific neutralizing antibody abolished the effects of the soluble receptor. Finally, supernatant from synoviocytes stimulated by IL-6 plus its soluble receptor blocked almost completely the collagenolytic activity of supernatant from IL-1-induced synoviocytes. These observations indicate that IL-6 and its soluble receptor have a protective role in the metabolism of cartilage. Given the high levels of soluble receptor in synovial fluid and the marked induction of IL-6 by IL-1 or TNF-␣, it is likely that IL-6 and its soluble receptor are critical in controlling the catabolic effects of pro-inflammatory cytokines.Tissue inhibitors of metalloproteases (TIMPs) 1 are important and specific inhibitors of matrix metalloproteases (MMPs) activity (1). These two classes of molecules play a crucial role in the fine regulation of extracellular matrix turnover, which is altered in most pathological states associated with abnormal extracellular matrix formation (i.e. fibrotic diseases) or tissue destruction (i.e. rheumatoid arthritis). TIMP proteins can bind either to the active site of MMPs, thus blocking access to the substrate, or to the precursor form, blocking further activation.So far, the sequences coding for four human TIMPs (TIMP-1, -2, and -3 and, more recently, TIMP-4) have been identified (1-11). The expression of TIMP-1 proved to be both constitutive and inducible, whereas TIMP-2 appeared to be widely expressed but not inducible (1,12). A recent study indicates that TIMP-3 expression is also constitutive and inducible (13).TIMP-1 expression in differentiated chondrocytes and fibroblasts has been shown to regulated by a few growth factors or cytokines, among which transforming growth factor-␤ (TGF-␤) is considered to be the most important inducer (1,14). On the other hand, catabolic cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-␣ (TNF-␣), the main promoters of MMPs synthesis and matrix degradation, have a marked inhibitory effect on TIMP-1 expression by chondrocytes, although some results have shown that IL-1, depending on the conditions, can either stimulate or inhibit the synthesis of TIMP-1 (15-19). IL-6 was initially considered a pro-inflammatory cytokine like TNF-␣ and IL-1, because of its IL-1-like eff...

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“…For example, a proportion of families with the eye disease retinitis pigmentosa from our data base map to six different genetic loci. Also, because TIMP3 tissue expression is widespread (Wilde et al 1994), the association with nonretinal disease in families 1, 9, and 11 was thought possibly to imply that each would express a different TIMP3 mutation. Interestingly, TIMP1 is expressed in gingival tissues of periodontitis patients (Meikle et al 1994), and the relevance of a similar gum disease associated with TIMP3 needs to be investigated further.…”

Section: @ Genome Researchmentioning

confidence: 99%

Sorsby's fundus dystrophy in the British Isles: demonstration of a striking founder effect by microsatellite-generated haplotypes.

Wijesuriya¹,

Evans²,

Jay³

et al. 1996

Genome Res.

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Sorsby's fundus dystrophy {SFD} has been mapped to a genetic interval of 8 cM between loci D225275 and D22S278. A total of 15 families, unrelated on the basis of genealogy and expressing the SFD phenotype were identified from a large data base of genetic eye disease families originating from diverse parts of the British Isles. The identification of the same SerlSICys mutation cosegregating with disease in each family led us to consider the hypothesis of a founder effect being present. In all families studied, the same relatively infrequent allele (occurring in just 11°/0 of the control group} was associated with disease at marker locus D22S280. A highly significant disease-associated haplotype, spanning across 3 cM of the SFD locus, was conserved in 11 of the 15 families {68% of all affected chromosomes}; a further extended haplotype spanning up to 7 cM, was identified in 5 families {27% of SFD-associated chromosomes} and possibly represents the ancestral haplotype. This haplotype analysis has refined the TlhlP3 gene localization to a I-to 3-cM interval between marker loci D22S273 and D22S281 and provides strong evidence for a single mutational event being responsible for the majority of SFD identified in the British Isles.

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Cloning and Characterization of Human Tissue Inhibitor of Metalloproteinases-3

Cited by 30 publications

References 25 publications

Molecular Cloning and Characterization of Human Tissue Inhibitor of Metalloproteinase 4

Molecular Cloning and Characterization of Human Tissue Inhibitor of Metalloproteinase 4

Interleukin (IL)-6 and Its Soluble Receptor Induce TIMP-1 Expression in Synoviocytes and Chondrocytes, and Block IL-1-induced Collagenolytic Activity

Sorsby's fundus dystrophy in the British Isles: demonstration of a striking founder effect by microsatellite-generated haplotypes.

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