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PubMed1996

Dysplasia expresses altered nuclear matrix protein composition in human ulcerative colitis.

We compared nuclear matrix protein compositions (NMPS) in colonic tissue from three different patient groups: 1) normal controls; 2) ulcerative colitis (UC); and 3) ulcerative colitis with dysplasia (UC-dysplasia). NMPS were separated by two-dimensional electrophoresis using isoelectrofocusing and SDS-PAGE. Six specific NMPS (59,500 Kd, pI 6.6 and 6.3; 49,250 Kd, pI 7.4; 33,750 Kd, pI 7.5; 20,000 Kd, pI 7.5; and 19,000 Kd, pI 6.3) were identified in UC-dysplasia that were not found in normal controls nor in UC colonic tissue. These observations suggest that NMPS may serve as important biochemical markers of dysplasia in UC.

Colitis, Ulcerative↗
PubMed1996

Nuclear matrix bound DNA polymerase-beta in mouse fibrosarcoma: effect of gamma-radiation.

Nuclear matrices isolated from the mouse fibrosarcoma tumour cells contain the eukaryotic replicative enzyme DNA polymerase-alpha and the presumptive repair enzyme DNA polymerase-beta. Exposure of tumors to various doses of gamma-radiation (1.95 to 6.5 Gy) causes a 2-fold increase in the levels of only DNA polymerase-beta in the nuclear matrix. The increase in the levels of this enzyme is not discernible if the matrices are isolated 24 hr after irradiation. The rise in the levels of the repair enzyme DNA polymerase-beta could be indicative of radiation stress response of the tumour cells and their repair ability.

Animals↗
PubMed2000

Nuclear matrix protein (NMP) levels in patients with acute pancreatitis.

Nuclear matrix protein (NMP) is an index of apoptosis. We measured NMP in 22 patients with acute pancreatitis and investigated the relationship between severity and NMP. We also measured tumor necrosis factor-alpha (TNF-alpha) and investigated the relationship between NMP and TNF-alpha. The NMP value increased significantly as the pancreatitis became more increasingly severe, and the NMP values were significantly higher in the group with multiple organ dysfunction syndrome (MODS) than in the group without MODS. A comparison of the NMP values in the group that survived and the group that died revealed higher NMP values in the former. A significant correlation was found between the NMP values and the TNF-alpha values, suggesting that apoptosis may contribute to the pathophysiology of acute pancreatitis.

Acute Disease↗
PubMed1997

Comparison of urine collection methods for evaluating urinary nuclear matrix protein, NMP22, as a tumor marker.

PURPOSE: The nuclear matrix protein, NMP22, has been shown to be a useful tumor marker for identifying patients with a high likelihood of rapid recurrence of transitional cell carcinoma of the urinary tract after surgical treatment. Currently measurement of NMP22 involves 3 urine voids collected during a 24-hour period, which are pooled and assayed as a single sample. This study was performed to determine whether any single void would yield similar results to the pooled 3-void sample. MATERIALS AND METHODS: A total of 2,018 urine samples (3 voids per sample) was included in the study. All analyses were performed using the nonparametric Wilcoxon signed rank test for matched pairs. RESULTS: Analysis showed that the NMP22 level of a single void collected between midnight and noon was similar to the NMP22 level of the pooled 3-void sample. Receiver operating characteristics curves of the midnight-to-noon single void and the pooled 3-void sample were similar for predicting recurrence postoperatively in patients with urinary tract transitional cell carcinoma. CONCLUSIONS: One void collected between midnight and noon compares favorably with the current 3-void collection method for determining NMP22 levels in urine.

Biomarkers, Tumor↗
PubMed1987

Radiolabelling of DNA/polypeptide complexes in isolated bulk DNA and in residual nuclear matrix DNA by nick-translation.

Conditions are described that allow 32P-radiolabelling and detection of tight complexes between DNA and polypeptides by nick-translation. Prolonged nick-translation of purified bulk DNA results in radiolabelled complexes migrating on SDS-polyacrylamide gels with apparent molecular weights of 68 kd and 54 kd respectively. Residual nuclear matrix DNA which is not accessible to DNase I on the nuclear level becomes accessible to radiolabelling by nick-translation on the nuclear matrix level. In this case the in situ radiolabelled complexes migrate on SDS-polyacrylamide gels with apparent molecular weights of 68 kd and 100 kd. The DNA/polypeptide complexes are stable during treatments with SDS, beta-mercapto ethanol and alkali which points to covalent bonds between the polypeptides and DNA strands.

Cell Nucleus↗
PubMed2000

Nuclear matrix provides linkage sites for translocated NF-kappa B: morphological evidence.

In response to the binding of extracellular ligands to cell surface receptors, multiple transcription factors are activated in the cytoplasm and translocated into the nucleus where they exert positive or negative control over cellular genes. The human transcription factor NF-kappa B family regulates the expression of a large number of genes involved in the host defence mechanism. They are typically present in the cytoplasm bound to the inhibitory I kappa B proteins. The activation of NF-kappa B involves the signal-induced degradation of these proteins, allowing NF-kappa B to translocate to the nucleus. In this study, by multiparametric analysis, we recognise in RPMI-8402 DMSO-activated cells the intracellular movement of transcription factor NF-kappa B providing its definite intranuclear collocation. Intact cells, purified nuclei and nuclear matrix preparations after 4 h of treatment were processed for morphological and biochemical analyses. Light and electron microscope observations show, in untreated cells, the presence of NF-kappa B protein homogeneously retained in the cytoplasm. Treated cells display a massive presence of NF-kappa B at the nuclear level bound to the interchromatin region. Immunoblotting of the same specimens confirms the strong association of NF-kappa B with the nuclear scaffold. Taken together, the data presented in this manuscript support a model where DMSO treatment provokes the cleavage and translocation of NF-kappa B from the cytoplasm to the nucleus and, in particular, in the proteinaceous network of the nuclear matrix sustaining the active role of this subcellular structure on regulation of eukaryotic gene expression.

Biological Transport↗
PubMed2002

Necdin interacts with the ribonucleoprotein hnRNP U in the nuclear matrix.

Necdin is expressed predominantly in terminally differentiated neurons, and its ectopic expression suppresses cell proliferation. We screened a cDNA library from neurally differentiated embryonal carcinoma P19 cells for necdin-binding proteins by the yeast two-hybrid assay. One of the positive clones contained cDNA encoding a carboxyl-terminal portion of heterogeneous nuclear ribonucleoprotein U (hnRNP U), a nuclear matrix-associated protein that interacts with chromosomal DNA. We isolated cDNA encoding full-length mouse hnRNP U to analyze its physical and functional interactions with necdin. The necdin-binding site of hnRNP U was located near a carboxyl-terminal region that mediated the association between hnRNP U and the nuclear matrix. In postmitotic neurons, endogenously expressed necdin and hnRNP U were detected in the nuclear matrix and formed a stable complex. Ectopically expressed necdin was concentrated in the nucleoli, but coexpressed hnRNP U recruited necdin to the nucleoplasmic compartment of the nuclear matrix. Furthermore, under the same conditions necdin and hnRNP U cooperatively suppressed the colony formation of transfected SAOS-2 cells. These results suggest that necdin suppresses cell proliferation through its interaction with hnRNP U in the specific subnuclear structure.

Animals↗
PubMed2003

Gfi-1 attaches to the nuclear matrix, associates with ETO (MTG8) and histone deacetylase proteins, and represses transcription using a TSA-sensitive mechanism.

Gfi-1 and Gfi-1B can repress transcription and play important roles in hematopoietic cell survival and differentiation. Although these proteins are known to bind DNA through a C-terminal zinc-finger domain and may require an N-terminal SNAG domain (SNAIL/Gfi-1) to repress transcription, the mechanism by which Gfi-1 and Gfi-1B act is unknown. A first step towards understanding the mechanism by which these proteins repress transcription is to identify interacting proteins that could contribute to transcriptional repression. ETO (also termed MTG8), was first identified through its involvement in the (8;21) translocation associated with acute myelogenous leukemia. It attaches to the nuclear matrix and associates with histone deacetylases and the co-repressors N-CoR, SMRT, and mSin3A, and may act as a co-repressor for site-specific transcriptions factors. In this report we demonstrate that Gfi-1 interacts with ETO and related proteins both in vitro and in vivo and with histone deacetylase proteins in vivo. We observed that a portion of Gfi-1 and Gfi-1B associated with the nuclear matrix, as is the case with ETO. Moreover, Gfi-1 and ETO co-localize to punctate subnuclear structures. When co-expressed in mammalian cells, Gfi-1 associates with histone deacetylse-1 (HDAC-1), HDAC-2, and HDAC-3. These data identify ETO as a partner for Gfi-1 and Gfi-1B, and suggest that Gfi-1 proteins repress transcription through recruitment of histone deacetylase-containing complexes.

Cells, Cultured↗
PubMed1986

Preferential binding of the carcinogen benzo[a]pyrene to DNA in active chromatin and the nuclear matrix.

Rat liver nuclei or hepatocytes were incubated with the proximate carcinogen, benzo[a]pyrene (BP) and its ultimate carcinogen, anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). Following carcinogen exposure, nuclei were fractionated by micrococcal nuclease digestion and stepwise extraction to yield an active chromatin fraction enriched in transcribed versus non-transcribed genes, a bulk chromatin fraction, a high-salt-extracted chromatin fraction and a nuclear matrix fraction containing elevated concentrations of transcribed and nontranscribed genes. BP binds more readily to DNA of active chromatin and nuclear matrix than to bulk chromatin. Since low concentrations of BPDE also selectively damage active chromatin and matrix DNA, selectivity is not due to the subnuclear location of enzymes which activate BP to BPDE. Higher BPDE concentrations cause more uniform DNA damage. Selective carcinogen attack may result from an accessible DNA conformation in active chromatin and matrix or from partitioning of carcinogen in the nuclear membrane.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2005

In silico and wet-bench identification of nuclear matrix attachment regions.

Chromatin loops are tethered at discrete regions that are approx 100-1000 bp in length. These regions of attachment serve as specific sequence landmarks, anchoring the DNA to the fibers of the chromosomal scaffold. It has been estimated that our genome contains 70,000 nuclear matrix attachment sites that serve as a dynamic nuclear organizer in both the interphase and metaphase cell. Approximately 30,000-40,000 matrix attachment regions (MARs) serve as origins of replication. MARs can also be associated with chromosomal segments densely populated with transcription factor-binding sites. This may facilitate transcription that is initiated within the region of the chromosome coincident with the surface of the nuclear matrix. Assuming an average somatic loop size of 100 kb, it is reasonable to propose that each cell utilizes 30,000 MARs to anchor each of the approx 20,000 active genic domains. This is sufficient to encompass the 30,000 functional genes in our genome that exist as members of single or multigenic families, each constituting a single chromatin domain. With the sequencing phase of various genome projects complete, in silico tools are being developed to identify the long-range control elements that modulate gene expression. This information is necessary to specifically target the time-intensive wet-bench verification and expression experiments that will provide a unified understanding of gene regulation. In this chapter we review some of the in silico strategies that are currently available and a new in vivo method based on the real-time polymerase chain reaction, to assess regions of matrix association.

Actins↗
PubMed1997

Nuclear matrix proteins as malignant markers in squamous cell carcinoma of the head and neck.

OBJECTIVE: To test the hypothesis that transformation of normal upper aerodigestive mucosa to squamous cell carcinoma of the head and neck (SCCHN) is associated with specific changes in nuclear matrix (NM) proteins. DESIGN: Retrospective, nonrandomized investigation using a cellular fractionation sequence followed by 2-dimensional gel electrophoresis analysis of NM proteins. SUBJECTS: Nuclear matrix proteins were extracted from a cohort of 12 pathologic SCCHN specimens and 5 normal specimens of oropharyngeal mucosa. RESULTS: All SCCHN specimens examined expressed 11 NM proteins that were not detected in normal mucosa. Conversely, at least 4 NM proteins that were expressed by all specimens of normal mucosa were absent from all SCCHN tumors. Seven NM proteins were common to carcinomas and normal specimens. Spindle cell histological variants of squamous cell carcinoma had distinct NM patterns. CONCLUSIONS: Malignant transformation of normal upper aerodigestive mucosa to SCCHN is associated with specific changes in NM composition. These data suggest that different NM proteins might serve as specific tumor markers.

Antigens, Nuclear↗
PubMed1984

Androgen binding sites on nuclear matrix of normal and hyperplastic human prostate.

To further characterize human prostatic androgen receptor, nuclei were isolated from normal prostate (no. = 3) and benign prostatic hyperplasia specimens (no. = 10). High ionic strength (0.6 M KCl) treatment of nuclei released nuclear extractable androgen receptor and DNase I digestion then yielded nuclear matrices. Androgen receptor was quantified in the nuclear extract and nuclear matrix preparations by Scatchard analysis of specific R1881 binding. Only 1 of the 3 normal tissues had extractable androgen receptor (113 fmol. per gm. of tissue) while the mean concentration of extractable androgen receptor for BPH was 189 fmol. per gm. of tissue. The mean concentrations of matrix-bound androgen receptor were 325 fmol. per gm. of tissue and 548 fmol. per gm. of tissue for normal and hyperplastic prostate, respectively. The androgen binding sites on nuclear matrix may represent the functional intranuclear androgen receptor and a characterization of these sites may provide an understanding of the etiology of BPH.

Adult↗
PubMed1994

In vitro heat exposure induces a redistribution of nuclear matrix proteins in human K562 erythroleukemia cells.

By using both conventional and confocal laser scanning microscopy with three monoclonal antibodies recognizing nuclear matrix proteins we have investigated by means of indirect fluorescence whether an incubation of isolated nuclei at the physiological temperature of 37 degrees C induces a redistribution of nuclear components in human K562 erythroleukemia cells. Upon incubation of isolated nuclei for 45 min at 37 degrees C, we have found that two of the antibodies, directed against proteins of the inner matrix network (M(r) 125 and 160 kDa), gave a fluorescent pattern different from that observed in permeabilized cells. By contrast, the fluorescent pattern did not change if nuclei were kept at 0 degrees C. The difference was more marked in case of the 160-kDa polypeptide. The fluorescent pattern detected by the third antibody, which recognizes the 180-kDa nucleolar isoform of DNA topoisomerase II, was unaffected by heat exposure of isolated nuclei. When isolated nuclear matrices prepared from heat-stabilized nuclei were stained by means of the same three antibodies, it was possible to see that the distribution of the 160-kDa matrix protein no longer corresponded to that observable in permeabilized cells, whereas the fluorescent pattern given by the antibody to the 125-kDa polypeptide resembled that detectable in permeabilized cells. The 180-kDa isoform of topoisomerase II was still present in the matrix nucleolar remnants. We conclude that a 37 degrees C incubation of isolated nuclei induces a redistribution of some nuclear matrix antigens and cannot prevent the rearrangement in the spatial organization of one of these antigens that takes place during matrix isolation in human erythroleukemia cells. The practical relevance of these findings is discussed.

Antibodies↗
PubMed1990

Probing the sulfhydryl groups of nuclear matrix proteins with 6-iodoacetamidofluorescein.

Rat liver nuclear matrices were reacted with the fluorescent dye 6-iodoacetamidofluorescein and the matrix proteins were then separated by one and two-dimensional polyacrylamide gel electrophoresis. Upon transillumination with U.V. light it was possible to see that several proteins had reacted with the dy, thus indicating the presence of free -SH groups. This labelling technique allowed the detection of a large number of proteins, being several folds more sensitive than conventional Coomassie Blue staining, as demonstrated by two-dimensional electrophoretical separation. If nuclear matrices were treated with reducing agents before being reacted with 6-iodoacetamidofluorescein, the fluorescence increased with about the same intensity in all the protein bands. It is proposed that 6-iodoacetamidofluorescein can be used as a specific and very sensitive probe to study the -SH groups of nuclear matrix proteins.

Animals↗
PubMed2003

Identification of calreticulin as a nuclear matrix protein associated with human colon cancer.

Colon cancer is one of the most common malignancies among populations in the United States and Western Europe, and one of the leading causes of worldwide morbidity and mortality due to cancer. The early detection of colon cancer is central to the effective treatment of this disease and early detection markers are needed. We have demonstrated that high-resolution two-dimensional gel analysis of nuclear matrix proteins (NMPs) demonstrated a specific oncological fingerprint of colon cancer. Utilizing this approach, four proteins specific for colon cancer was identified. Additionally, one protein was expressed much more strongly in colon cancer compared to adjacent and normal donor tissue. The amino acid composition of this protein revealed sequence similarity with calreticulin. The multi-functional protein, calreticulin, is normally found in the lumen of the endoplasmic reticulum although some reports have described a nuclear localization of the protein. The aim of this study was to confirm the identity of the protein as calreticulin as well as to evaluate the localization of calreticulin in the nuclear matrix of colon cancer tissue.

Adenocarcinoma↗
PubMed2006

Bone formation: The nuclear matrix reloaded.

In this issue of Cell, Grosschedl and colleagues (Dobreva et al., 2006) report that the nuclear matrix protein Satb2 represses Hoxa2 expression and acts with other regulatory proteins to promote osteoblast differentiation. This work suggests a molecular mechanism that enables the integration of patterning and differentiation during bone formation.

Animals↗
PubMed2000

The nuclear matrix protein CDP represses hepatic transcription of the human cholesterol-7alpha hydroxylase gene.

To date, the molecular mechanisms that govern hepatic-specific transcription of the human cholesterol 7alpha-hydroxylase (CYP7A1) gene are poorly understood. We recently reported that the region extending from -1888 to +46, which includes the promoter, is not capable of conferring expression to human CYP7A1 promoter lacZ transgenes in the livers of mice, but that expression is observed with transgenes containing the entire structural gene. To locate liver-specific elements in other segments of the human gene, DNase I hypersensitivity studies were performed with transcriptionally active, liver-derived HepG2 cells and with transcriptionally inactive HeLa cells. Three DNase I hypersensitivity sites were detected within the first intron of the human CYP7A1 gene, but only in HepG2 cells. Transient transfection experiments with HepG2 cells revealed a transcriptional repressor within intron 1. Five binding sites for the CAAT displacement protein (CDP) were detected within intron 1. Since CDP is a nuclear matrix protein, two methods were employed to localize nuclear matrix attachment sites within intron 1 of the human CYP7A1 gene. A matrix attachment site was found throughout the entirety of intron 1. Gel retardation experiments and cell transfection studies provided evidence for the repression mechanism. Repression is achieved by displacement by CDP of two hepatic activators, namely HNF-1alpha and C/EBPalpha, that bind to three different sites within intron 1. Additionally, CDP represses transactivation mediated by these two activators.

Animals↗
PubMed1995

The nuclear matrix phosphoprotein p255 associates with splicing complexes as part of the [U4/U6.U5] tri-snRNP particle.

The monoclonal antibody CC3 recognizes a phosphorylated epitope present on an interphase protein of 255 kDa. Previous work has shown that p255 is localized mainly to nuclear speckles and remains associated with the nuclear matrix scaffold following extraction with non-ionic detergents, nucleases and high salt. The association of p255 with splicing complexes is suggested by the finding that mAb CC3 can inhibit in vitro splicing and immunoprecipitate pre-messenger RNA and splicing products. Small nuclear RNA immunoprecipitation assays show that p255 is a component of the U5 small nuclear ribonucleoprotein (snRNP) and the [U4/U6.U5] tri-snRNP complex. In RNase protection assays, mAb CC3 immunoprecipitates fragments containing branch site and 3' splice site sequences. As predicted for a [U4/U6.U5]-associated component, the recovery of the branch site-protected fragment requires binding of U2 snRNP and is inhibited by EDTA. p255 may correspond to the previously identified p220 protein, the mammalian analogue of the yeast PRP8 protein. Our results suggest that changes in the phosphorylation of p255 may be part of control mechanisms that interface splicing activity with nuclear organization.

Animals↗