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PubMed2005

MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells.

During pathologic vessel remodeling, vascular smooth muscle cells (VSMCs) embedded within the collagen-rich matrix of the artery wall mobilize uncharacterized proteolytic systems to infiltrate the subendothelial space and generate neointimal lesions. Although the VSMC-derived serine proteinases, plasminogen activator and plasminogen, the cysteine proteinases, cathepsins L, S, and K, and the matrix metalloproteinases MMP-2 and MMP-9 have each been linked to pathologic matrix-remodeling states in vitro and in vivo, the role that these or other proteinases play in allowing VSMCs to negotiate the three-dimensional (3-D) cross-linked extracellular matrix of the arterial wall remains undefined. Herein, we demonstrate that VSMCs proteolytically remodel and invade collagenous barriers independently of plasmin, cathepsins L, S, or K, MMP-2, or MMP-9. Instead, we identify the membrane-anchored matrix metalloproteinase, MT1-MMP, as the key pericellular collagenolysin that controls the ability of VSMCs to degrade and infiltrate 3-D barriers of interstitial collagen, including the arterial wall. Furthermore, genetic deletion of the proteinase affords mice with a protected status against neointimal hyperplasia and lumen narrowing in vivo. These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix.

Animals↗

PubMed1994

Modulation of production of matrix metalloproteinases from ovine endometrial cells by ovine trophoblast interferon.

Ovine trophoblast interferon modulates the secretion of a number of proteins by ovine endometrium, but only one of these proteins has so far been identified. We examined the effects of trophoblast interferon on the secretion of matrix metalloproteinase-1, -2 and -3 by cultured ovine endometrial cells and determined whether they are mediated via effects on prostaglandin synthesis. Both ovine trophoblast interferon (30 ng ml-1) and human recombinant interferon alpha (50 U ml-1) inhibited the production of latent matrix metalloproteinase-1 and -3 (P < 0.05), as measured by enzyme assays, but had no effect on the secretion of latent matrix metalloproteinase-2. These inhibitory effects were not overcome by PGE2 or PGF2 alpha (each 10 mumol l-1) either alone or in combination. Indomethacin (12 mumol l-1) similarly inhibited the production of latent matrix metalloproteinase-1 and -3, but production was partially restored by adding the prostaglandins either singly or in combination. PGE2 and PGF2 alpha together had no effect on enzyme production. These data were confirmed by gelatin and casein zymography. Northern analysis showed a 4.5-fold increase in the abundance of specific mRNA for latent matrix metalloproteinase-1 following treatment of cells with phorbol myristate acetate, but a marked decrease following interferon treatment. Thus, ovine trophoblast interferon inhibits the production of the latent forms of matrix metalloproteinase-1 and -3 by ovine endometrial cells, and this is independent of its effect on prostaglandin production.

Animals↗

PubMed2001

Induction of metalloproteinases by glomerular mesangial cells stimulated by proteins of the extracellular matrix.

Human glomerular mesangial cells (HMC) are embedded in the mesangial matrix (MM) and control its turnover through a dynamic equilibrium between synthesis and degradation. Degradation is controlled by matrix metalloproteinases (MMP), whose activity has been causally implicated in the progression of glomerular disease. In other systems, MMP secretion may be directly affected by exposure to specific matrix proteins. The present study, therefore, investigated the effect of different matrix components on the adherence of HMC and on their secretion and activation of the gelatinases MMP2 and MMP9. HMC adhered strongly (quantified using crystal violet staining) to collagen IV and collagen I (P < 0.01, relative to binding to control, bovine serum albumin (BSA)-coated wells) and to a lesser extent to gelatin IV and fibronectin (P < 0.05). Binding to vitronectin and laminin was not statistically different to control wells. After the addition of these matrix proteins (0.1 microg/ml to 100 microg/ml) to growth-arrested HMC for 72 h, zymography of the conditioned medium established that only fibronectin and collagens I and IV dose-dependently increased latent (72 kD) MMP2 secretion and activation. Fibronectin, however, also induced the secretion of MMP9. Membranes from HMC that had been co-cultured with fibronectin for 72 h were prepared to investigate whether the activation of MMP2 in this system was due to the action of membrane-type (MT)-MMP. When incubated with latent MMP2 for times up to 24 h, these membranes activated the enzyme in a time- and dose-dependent manner. The results demonstrate that specific matrix components increased the secretion of MMP2 and MMP9 from HMC. In addition, MT-MMP activity, selectively induced by fibronectin, was implicated in the activation of the secreted proteinases.

Animals↗

PubMed2000

Effects of interleukin-1beta and tumor necrosis factor-alpha on expression of matrix-related genes by cultured equine articular chondrocytes.

OBJECTIVE: To determine the effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) on expression and regulation of several matrix-related genes by equine articular chondrocytes. SAMPLE POPULATION: Articular cartilage harvested from grossly normal joints of 8 foals, 6 yearling horses, and 8 adult horses. PROCEDURE: Chondrocytes maintained in suspension cultures were treated with various doses of human recombinant IL-1beta or TNF-alpha. Northern blots of total RNA from untreated and treated chondrocytes were probed with equine complementary DNA (cDNA) probes for cartilage matrix-related genes. Incorporation of 35S-sulfate, fluorography of 14C-proline labeled medium, zymography, and western blotting were used to confirm effects on protein synthesis. RESULTS: IL-1beta and TNF-alpha increased steady-state amounts of mRNA of matrix metalloproteinases 1, 3, and 13 by up to 100-fold. Amount of mRNA of tissue inhibitor of metalloproteinase-1 also increased but to a lesser extent (1.5- to 2-fold). Amounts of mRNA of type-II collagen and link protein were consistently decreased in a dose-dependent manner. Amount of aggrecan mRNA was decreased slightly; amounts of biglycan and decorin mRNA were minimally affected. CONCLUSIONS AND CLINICAL RELEVANCE: Treatment of cultured equine chondrocytes with IL-1beta or TNF-alpha resulted in marked alterations in expression of various matrix and matrix-related genes consistent with the implicated involvement of these genes in arthritis. Expression of matrix metalloproteinases was increased far more than expression of their putative endogenous inhibitor. Results support the suggestion that IL-1beta and TNF-alpha play a role in the degradation of articular cartilage in arthritis.

Animals↗

PubMed1998

Basic matrices in the analysis of non-covalent complexes by matrix-assisted laser desorption/ionization mass spectrometry.

A number of potential matrix candidates were investigated with regard to the importance of the pH in the matrix-assisted laser desorption/ionization mass spectrometry (MALDI/MS) analysis of non-covalently bound protein complexes. The matrices examined were 2,5-dihydroxybenzoic acid (DHB), 4-hydroxy-alpha-cyanocinnamic acid (HCCA), 2-aminonicotinic acid (ANA), 4-nitroaniline (NA), 2-amino-4-methyl-5-nitropyridine (AMNP) and 3-hydroxypicolinic acid (HPA). In solution these matrix compounds permitted the preparation of MALDI samples at pH in the range 2-7. Among the matrices tested, complex formation, by specific non-covalent interactions, could only be observed when HPA (pH 3.8) was used as the matrix for the MALDI analysis. Under these conditions, specific non-covalent complex formation of recombinant streptavidin and glutathione-S-transferases were observed but not for human hemoglobin. The MALDI spectra obtained with the neutral compounds ANA (pH 4.4), NA (pH 6.4) and AMNP (pH 7.1) as matrices contain only peaks of the subunit with no signal of the non-covalent bound complexes present. Considering the results obtained in this study with basic and acidified matrix materials, there does not appear to be a strong correlation between the pH of the matrix solution and the utility of a matrix for the analysis of non-covalently bound complexes.

Chymotrypsinogen↗

PubMed1999

Insight into absorption of radiation/energy transfer in infrared matrix-assisted laser desorption/ionization: the roles of matrices, water and metal substrates.

Although the ionization/desorption mechanisms in matrix-assisted laser desorption/ionization (MALDI) remain poorly understood, there is a clear difference between the energy absorption processes in the ultraviolet (UV) and infrared (IR) modes of operation. UV-MALDI demands an on-resonance electronic transition in the matrix compound, whereas results presented here support earlier work showing that a corresponding resonant vibrational transition is not a requirement for IR-MALDI. In fact, data from the present study suggest that significant absorption of radiant energy by a potential matrix impairs its performance, although this observation is at variance with some other reports. For example, sinapinic acid, with an IR absorption maximum close to the 2.94 micrometer wavelength of the Er-YAG laser, has been little used as an IR-MALDI matrix. By contrast, succinic acid, with much lower IR absorption and no history of use in UV-MALDI as it has no UV absorption at the wavelength of common UV lasers, has become widely recognized as a good general purpose matrix for IR-MALDI. Despite reports by others that glycerol is an effective matrix for IR-MALDI, we find that glycerol, which also absorbs strongly at 2.94 micrometer, is useful only if applied as a very thin film. Thus the cumulative evidence for the role of the matrix in IR-MALDI appears confusing and often contradictory. Water has been postulated to be a major contributor to the absorption of energy in IR-MALDI. Consistent with this, we find that samples dried from D(2)O, which does not absorb at 2.94 micrometer, give spectra of inferior quality compared with the same samples from H(2)O. Similarly, samples dried under vacuum, that probably contain less water than those dried in the open laboratory, give weaker and more erratic spectra. Another potential participant in energy absorption and energy transfer is the surface of the metal support, an alternative mechanism for IR-MALDI, for which some evidence is presented here.

Chemical Phenomena↗

PubMed1996

A highly porous 3-dimensional polyphosphazene polymer matrix for skeletal tissue regeneration.

Current methods for the replacement of skeletal tissue in general involve the use of autografts or allografts. There are considerable drawbacks in the use of either of these tissues. In an effort to provide an alternative to traditional graft materials, a degradable 3-dimensional (3-D) osteoblast cell-polymer matrix was designed as a construct for skeletal tissue regeneration. A degradable amino acid containing polymer, poly[(methylphenoxy)(ethyl glycinato) phosphazene], was synthesized and a 3-D matrix system was prepared using a salt leaching technique. This 3-D polyphosphazene polymer matrix system, 3-D-PHOS, was then seeded with osteoblast cells for the creation of a cell-polymer matrix material. The 3-D-PHOS matrix possessed an average pore diameter of 165 microns. Environmental scanning electron microscopy revealed a reconnecting porous network throughout the polymer with an even distribution of pores over the surface of the matrix. Osteoblast cells were found attached and grew on the 3-D-PHOS at a steady rate throughout the 21-day period studied in vitro, in contrast to osteoblast growth kinetics on similar, but 2-D polyphosphazene matrices, that showed a decline in cell growth after 7 days. Characterization of 3-D-PHOS osteoblastpolymer matrices by light microscopy revealed cells growing within the pores as well as on surface of the polymer as early as day 1. This novel porous 3-D-PHOS matrix may be suitable for use as a bioerodible scaffold for regeneration of skeletal tissue.

Animals↗

PubMed1996

Developmental changes in transcription factors associated with the nuclear matrix of chicken erythrocytes.

The nuclear matrix has roles in organizing nuclear DNA and in controlling transcription. Transcription factors are associated with the nuclear matrix, with the spectra of transcription factors differing from one cell type to another. In this study we identified the transcription factors and enzymes functioning in the regulation of gene expression that were associated with nuclear matrix and nonmatrix nuclear fractions in erythrocytes isolated from chick embryos at different stages of development, anemic and normal adult birds. We found that the primitive erythroid nuclear matrix had the greatest histone deacetylase activity and highest levels of several transcription factors, including GATA-1, CACCC-binding proteins, and NF1. These transcription factors have key roles in erythroid-specific gene expression. The levels of these transcription factors were lower in the nonmatrix and matrix fractions isolated from definitive erythrocytes. For primitive and definitive erythrocytes, the level of CACCC-binding proteins in the nuclear matrix fraction was greater than that of Sp1. The relative levels of these transcription factors were reversed in the nonmatrix fraction. Casein kinase II was not found in erythroid nuclear matrices. The observed erythroid lineage specific alterations in erythroid nuclear matrix transcription factor composition and abundance may be involved in erythroid-specific gene expression.

Animals↗

PubMed1997

Heparan sulfate-binding peptide promotes the deposition of proteoglycans in the extracellular matrix.

A synthetic peptide, which was shown to bind extracellular matrix heparan sulfate chains with a high degree of affinity and specificity [Colburn et al. (1996): Arch Biochem Biophys 325:129-138], has now been found to promote the transfer and the deposition of endothelial cell surface proteoglycans in the extracellular matrix. The peptide also induces preferential binding of extracellular matrix heparan sulfate proteoglycans, which have been added to the supernatant growth medium, and the requirement for its presence is stringent in that only a negligible amount of proteoglycans are bound to the cell layer in the absence of the peptide. In addition, antibodies directed against the peptide detect the accumulation of the peptide in the matrix compartment where the peptide is found associated with the proteoglycans transferred from the cell surface. The sequence of events induced by the peptide appears to be an extension of a naturally occurring process since proteoglycans with properties similar to those of the species ordinarily present in the extracellular matrix have been observed to transfer from the cell surface to the matrix during a pulse-chase experiment. We suggest that formation of the complex peptide-proteoglycan with consequent displacement of the proteoglycan from its anchorage on the cell initiates the process of transfer of the heparan sulfate-bound peptide from the cell surface to the extracellular matrix.

Animals↗

PubMed1999

Stable transfection of human fetal chondrocytes with a type II procollagen minigene: expression of the mutant protein and alterations in the structure of the extracellular matrix in vitro.

OBJECTIVE: To perform stable transfections of human chondrocytes under conditions that allow the maintenance of the chondrocyte-specific phenotype, and to examine the effects of the stable transfection of a mutated type II procollagen gene (COL2A1) on the structure of the cartilaginous extracellular matrix produced in vitro. METHODS: A type II procollagen minigene that lacks exons 16-27 was stably transfected into human fetal epiphyseal chondrocytes in vitro. Expression of the minigene was detected by reverse transcriptase-polymerase chain reaction, and the encoded protein was identified by Western blot with a human type II collagen-specific antibody. The cartilaginous extracellular matrix produced by the cultured transfected chondrocytes was characterized using histochemical staining, polarized light microscopy analysis, and transmission electron microscopy. RESULTS: A shortened type II collagen encoded by the transfected minigene was biosynthesized and produced in the cultures of transfected cells. Histologic analyses demonstrated a more dense, negatively charged cartilaginous matrix in control cultures. In contrast, COL2A1 minigene-transfected cultures were more cellular, were populated with cells of irregular shape and less-chondrocytic appearance, contained abundant intracellular dense granules, and were surrounded by a less-dense matrix. Polarized light microscopy and transmission electron microscopy revealed a well-organized collagen fibrillar matrix in untransfected, control chondrocyte cultures, while the matrix in the transfected cultures was less birefringent and contained numerous truncated collagen fibrils. CONCLUSION: The findings illustrate the feasibility of gene transfer into human fetal chondrocytes under conditions that allow the preservation of their specific phenotype, and also shed light on the function of type II collagen in the maintenance of the structural integrity of articular cartilage matrix.

3T3 Cells↗

PubMed1986

In situ localization of lectin-binding glycoconjugates in the matrix of growth-plate cartilage.

In the distal hypertrophic zone of growth-plate cartilage, the pericellular matrix surrounding individual chondrocytes and the territorial matrix uniting chondrocytes into columnar groups are invaded by metaphyseal endothelial cells prior to osteogenesis. In the present study, lectin-binding glycoconjugates were analyzed in these two matrix compartments of growth-plate cartilage from Yucatan swine. Nine lectin-fluorescein conjugates were tested by a postembedment method on 1-micron-thick, nondecalcified, Epon-embedded sections. Chondrocytes in all cellular zones were surrounded by a pericellular matrix which showed positive binding for peanut agglutinin (PNA), ricin agglutinin (RCA-I), and soybean agglutinin (SBA). Binding by these lectins was sensitive to digestion with hyaluronidase, chondroitinase, and trypsin. Pericellular glyconconjugtes that bind RCA-I and concanvalin A (CONA) after periodic acid oxidation, and which were sensitive to trypsin but not to chondroitinase or hyaluronidase, were present in the hypertrophic cell zone. Within the territorial matrix, binding of lectins specific for galactose, N-acetylgalactosamine, and fucose showed gradients of intensity which became maximal at the last transverse septum. Lectin-binding histochemistry more precisely differentiated the microheterogeneity of glycoconjugate distribution within these two matrix compartments than has been possible with other histochemical techniques. Lectin-binding affinity is a potentially useful technique by which to isolate cartilage matrix macromolecules unique to specific cellular zones of the growth plate.

Animals↗

PubMed1989

In vitro reconstruction of a cartilage matrix granule network.

The cartilage extracellular matrix contains electron-dense granules and fine filaments when studied electron microscopically after staining with ruthenium red. The matrix granules contain proteoglycans, while the filaments are thought to represent hyaluronic acid. In the present study partial extraction of proteoglycans from the cartilage prior to staining reduced the density of matrix components to allow visualization of a well-developed network involving the matrix granules and hyaluronic acid filaments. The matrix granules frequently had multiple filamentous attachments and the network appeared to be formed by intersecting filaments with the matrix granules at points of intersection. A similar network was created in Sepharose CL-2B beads when proteoglycans, link proteins, and hyaluronic acid were concentrated in the beads. Elimination of any one of these components resulted in failure to form a complete network. Purified proteoglycan monomers alone were sufficient to create matrix granules in the beads. Filaments were seen only when hyaluronic acid was added to the beads. The nature of the network suggests that some type of association between separate aggregates is occurring both within cartilage and within the Sepharose CL-2B beads.

Animals↗

PubMed1992

Multiple glycoproteins localize to a particulate form of extracellular matrix in regions of the embryonic heart where endothelial cells transform into mesenchyme.

Cells derived from an epithelial-mesenchymal transformation within the atrioventricular canal and outflow tract are involved in the partitioning of the early embryonic heart into a four-chambered organ. This transformation process has been shown to proceed from an inductive interaction between the myocardium and competent, target endothelial cells within these regions of the heart. Interestingly, immunohistochemistry revealed the presence of fibronectin-positive particulates within the matrix of mesenchyme-forming regions (Mjaatvedt et al., 1987). This particulate matrix is extractable by EDTA and can elicit the epithelial-mesenchymal transformation in culture (Mjaatvedt and Markwald, 1989). Analysis of EDTA extracts of embryonic heart tissue revealed the presence of fibronectin and about 40 unidentified proteins, 6 of which appeared to be enriched in the biologically active 100,000g pellet fraction (Mjaatvedt and Markwald, 1989). Based on these and other data we have proposed that the particulate matrix is composed of a multicomponent complex of fibronectin and one or more of the low-molecular-weight proteins in this pellet. The purpose of the present study was to begin a biochemical characterization of the nonfibronectin proteins thought to be present in the matrix particulates. Given that many matrix constituents are glycoproteins, lectins were used to initially characterize the particulate constituents. Of the lectins tested, soybean agglutinin (SBA) was found to be specific only for matrix particulates. Histochemical analyses showed that SBA and antibodies against fibronectin colocalized regionally and temporally to the same matrix particulates in embryonic heart tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2006

Aspects of extracellular matrix remodeling in development and disease.

The extracellular matrix is the major constituent of organic matter in both plants and animals, where it provides the interface between individual cells. In most tissues, with some notable exceptions such as bone marrow, the volume of extracellular matrix equals or exceeds the volume of intracellular space and organelles, making matrix an abundant constituent through which cells exert their functions and receive cues. The matrix may therefore be considered the basic structural entity that supports the function of an organ, and in connective tissues the matrix is the organ itself to which function is tied throughout the life of its resident cells. In this review, a select number of proteinases involved in some of the more conspicuous matrix remodeling events of the mammalian organism are explored. Evidence from both animal models and human diseases is discussed in relation to normal physiological processes, including instances in which aberrant matrix remodeling leads to disease states.

Animals↗

PubMed1984

Integrity of the pericellular fibronectin matrix of fibroblasts is independent of sulfated glycosaminoglycans.

The pericellular matrix fibers of cultured human fibroblasts contain fibronectin, other glycoproteins, and heparan and chondroitin sulfate proteoglycans. In the present study, cell-free pericellular matrices were isolated from metabolically labeled fibroblast cultures. The isolated matrices were digested with heparinase from Flavobacterium heparinum, and then analyzed for sulfated glycosaminoglycans (GAGs). Nitrous acid degradation was used to distinguish the N-sulfated GAGs (heparan sulfate) from chondroitin sulfate. Fibronectin and the other major matrix polypeptides were studied using gel electrophoresis, enzyme immunoassay and immunofluorescence. Upon heparinase digestion, greater than 95% of sulfated GAGs were degraded in the matrix without detectable release of fibronectin or other matrix polypeptides or alteration of the fibrillar matrix structure. We conclude that in fibroblast cultures the integrity of the fibrillar matrix is independent of sulfated GAGs. Together with earlier observations, this suggests that filamentous polymerization of fibronectin forms the backbone of early connective tissue matrix.

Cells, Cultured↗

PubMed1994

Cellular and matrix changes before and at the time of calcification in the growth plate studied in vitro: arrest of type X collagen synthesis and net loss of collagen when calcification is initiated.

To understand the growth, maturation, and regulation of growth plate chondrocytes, it is necessary to isolate the different chondrocytes into distinct subpopulations of maturational development. Five subpopulations (A-E) of bovine fetal growth plate chondrocytes were separated by discontinuous gradient centrifugation. Four subpopulations (B, C, D, and E, from low to high density) with good viability were cultured at high density in microwells for up to 30 days. They all established an extensive extracellular matrix composed of proteoglycan and collagen. The largest and last dense cells in subpopulation B were the first to synthesize (at days 5-6) type X collagen and to calcify this matrix. Matrix calcification (formation of hydroxyapatite in the presence of sodium beta-glycerophosphate) always followed the initiation of type X synthesis. All the other subpopulations synthesized type X collagen and calcified their extracellular matrix. Although these events occurred in the same order, they were delayed according to the order of increasing cell size. These observations indicate that these subpopulations represent different stages in cellular maturation that lead to expression of the hypertrophic phenotype. Once mineral formation was well established, there was an increase in the matrix content of the C-propeptide of type II collagen (which is known to bind to hydroxyapatite and accumulate in calcifying extracellular matrix). This was accompanied by a reduction in the total collagen content, which accompanied an abrupt reduction in type X collagen synthesis, whereas type II collagen synthesis was largely maintained. These reductions in collagen content and type II collagen synthesis were not observed in the absence of calcification (beta-glycerophosphate omitted from culture). This new culture system recreates many of the sequential cellular and extracellular changes exhibited in situ during the development of the physis and provides new information about cellular and extracellular matrix changes that occur before and at the time of calcification.

Absorptiometry, Photon↗

PubMed1987

Comparison of basement membrane matrix degradation by purified proteases and by metastatic tumor cells.

We have examined the nature of biochemical degradation of an isolated basement membrane matrix (bovine lens capsule) using different methodologies. The first strategy was quantitation of the release of surface-bound 125I and a second the documentation by SDS-PAGE of the appearance of putative cleavage products and the loss of high-molecular-weight components from the matrix. Basement membrane matrix bands resolved on SDS-PAGE were identified by their protease sensitivities as well as by Western immunoblots using monoclonal antibodies developed for this study. Radioiodinated components were found predominantly at positions on the gel equivalent to 160-200 kd and 400 kd proteins. Since these labeled moieties were sensitive to bacterial collagenase digestion and stained with anticollagen type IV antibodies, they were determined to represent various configurations of collagen type IV. Several other lower-molecular-weight bands also stained with the anticollagen IV antibodies. Monoclonal antibodies reactive with laminin exhibited a complex staining pattern on the gels, which included the expected 200 and 400 kd components. We confirmed that lens capsule basement membrane contained only a single heparan sulfate glycosaminoglycan species, and tumor cell-induced glycosaminoglycan degradation within the basement membrane matrix was detected using cellulose acetate electrophoresis. Distinctive putative cleavage products were resolved on SDS-PAGE gels from matrices subjected to digestion by a variety of purified proteases as well as by metastatic tumor cells or their conditioned media. Tumor cells of different histiotypes produced different characteristic cleavage patterns, suggestive of the existence of several pathways of matrix degradation. Overall, primary tumor cells exhibited a greater degradative activity towards the basement membrane matrix than did long-term tissue culture-passaged cells. The same tumor cell line could exhibit considerably different patterns of both protein and glycosaminoglycan degradation depending on recent culture history. The relevance of these biochemical studies to the pathogenesis of malignant neoplasms is shown by: 1) the evaluation of degradative activities of B16 tumor cell populations exhibiting enhanced lung-colonizing phenotypes, and 2) the ability of a known antimetastatic moiety with antiprotease activity (Haementeria leech species salivary gland extract) to protect matrix components from degradation by tumor cell-conditioned medium.

Animals↗

PubMed1992

Homeotic protein binding sites, origins of replication, and nuclear matrix anchorage sites share the ATTA and ATTTA motifs.

Nuclear matrix organizes the mammalian chromatin into loops. This is achieved by binding of nuclear matrix proteins to characteristic DNA landmarks in introns as well as proximal and distal sites flanking the 5' and 3' ends of genes. Matrix anchorage sites (MARs), origins of replication (ORIs), and homeotic protein binding sites share common DNA sequence motifs. In particular, the ATTA and ATTTA motifs, which constitute the core elements recognized by the homeobox domain from species as divergent as flies and humans, are frequently occurring in the matrix attachment sites of several genes. The human apolipoprotein B 3' MAR and a stretch of the Chinese hamster DHFR gene intron and human HPRT gene intron shown to anchor these genes to the nuclear matrix are mosaics of ATTA and ATTTA motifs. Several origins of replication also share these elements. This observation suggests that homeotic proteins which control the expression level of many genes and pattern formation during development are components of the nuclear matrix. Thus, the nuclear matrix, known as the site of DNA replication, might sculpture the crossroads of the differential activation of origins during development and S-phase and the control of gene expression and pattern formation in embryogenesis.

Animals↗