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PubMed1995

The protein composition of Friend cell nuclear matrix stabilized by various treatments. Different recovery of nucleolar proteins B23 and C23 and nuclear lamins.

Using two-dimensional polyacrylamide gels stained with Coomassie blue we have studied the protein composition of the nuclear matrix obtained from mouse erythroleukemic nuclei kept at 0 degrees C throughout the isolation procedure to prepare the high ionic strength resistant fraction (control matrix) or stabilized in vitro or in vivo by different procedures prior to subfractionation (ie 37 degrees C incubation of isolated nuclei; sodium tetrathionate exposure of purified nuclei; heat shock of intact cells). When the matrix obtained from 37 degrees C incubated nuclei was compared with the control matrix, striking differences in the polypeptide pattern were seen if the protein was obtained in both cases from an equivalent number of nuclei. On the other hand, if the same amount of protein for both the samples was applied to the gels the differences were less evident. Sodium tetrathionate stabilization of isolated nuclei and heat shock of intact cells produced a matrix protein pattern that was very similar and differed from that of the in vitro heat-exposed matrix. Using specific polyclonal antisera, we demonstrate that nucleolar proteins B23/numatrin and C23/nucleolin were very abundant in the matrix obtained from chemically-treated nuclei or in vivo heat-stabilized nuclei but were recovered in very small amounts (B23) or completely absent (C23) in the matrix prepared from nuclei heated to 37 degrees C in vitro. Differences were seen also in the recovery of nuclear lamins, and especially lamin B, that was poorly represented in the sodium tetrathionate-stabilized matrix. The results demonstrate that in mouse erythroleukemia cells the increased recovery of nuclear matrix protein that is seen after in vitro heating of isolated nuclei is predominantly due to an additional recovery of the same types of polypeptides that are detected also in the absence of such a treatment. The data also indicate that in vivo heat shock of intact cells produces a nuclear matrix protein pattern that is more similar to the pattern seen after stabilization of purified nuclei with sodium tetrathionate and differs significantly from that obtained by exposing nuclei to 37 degrees C in vitro, unlike to that what previous reports have indicated.

Animals↗
PubMed1988

Nuclear matrix associated DNA is preferentially repaired in normal human fibroblasts, exposed to a low dose of ultraviolet light but not in Cockayne's syndrome fibroblasts.

In this study we addressed the questions as to whether repair is confined to the nuclear matrix compartment, analogous to replication and transcription and how repair events are distributed in DNA loops associated with the nuclear matrix. Pulse labelling of ultraviolet (254 nm) irradiated confluent human fibroblasts revealed that repair was preferentially located in nuclear matrix associated DNA in cells exposed to 5 J/m2. However, in cells exposed to 30 J/m2 repair approached a random distribution. The non-random distribution of repair label at 5 J/m2 was most pronounced directly after irradiation and gradually changed to a more random distribution within two hours after treatment. The results of pulse-chase experiments exclude the possibility of transient binding of repair sites to the matrix and favour the model of preferential repair of DNA sequences permanently associated with the nuclear matrix. Pronounced differences in distribution pattern of repair events in DNA loops were found among normal and UV-sensitive cell lines exposed to 5 J/m2. Repair in nuclear matrix associated DNA was 1.7 fold more efficient than in loop DNA in normal and xeroderma pigmentosum group D cells and over 3 fold in xeroderma pigmentosum group C cells. In Cockayne's syndrome fibroblasts repair in nuclear matrix DNA was found to be 2 fold less efficient than in loop DNA. This heterogeneity in distribution of repair correlates well with preferential removal of pyrimidine dimers from transcriptionally active DNA in normal and xeroderma pigmentosum group C cells and its absence in Cockayne's syndrome cells as recently reported by Mayne et al., 1988. The results suggest that Cockayne's syndrome cells have a defect in excision of UV-damage from transcriptionally active genes located proximal to the nuclear matrix. Xeroderma pigmentosum group C cells may possess a defect in DNA repair associated with chromatin regions outside transcriptionally active DNA.

Cell Nucleus↗
PubMed2005

Altered profiles of nuclear matrix proteins during the differentiation of human gastric mucous adenocarcinoma MGc80-3 cells.

AIM: To find and identify specific nuclear matrix proteins associated with proliferation and differentiation of carcinoma cells, which will be potential markers for cancer diagnosis and targets in cancer therapy. METHODS: Nuclear matrix proteins were selectively extracted from MGc80-3 cells treated with or without hexamethylamine bisacetamide (HMBA), and subjected to 2-D gel electrophoresis. The resulted protein patterns were analyzed by Melanie software. Spots of nuclear matrix proteins differentially expressed were excised and subjected to in situ digestion with trypsin. Peptide masses were obtained by matrix-assisted laser-desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) analysis and submitted for database searching using Mascot tool. RESULTS: The MGc80-3 cells were induced into differentiation by HMBA. There were 22 protein spots which changed remarkably in the nuclear matrix, from differentiation of MGc80-3 cells compared to control. Eleven of which were identified. Seven proteins--actin, prohibitin, porin 31HL, heterogeneous nuclear ribonucleoprotein A2/B1, vimentin, ATP synthase, and heat shock protein 60 were downregulated, whereas three proteins--heat shock protein gp96, heat shock protein 90-beta, and valosin-containing protein were upregulated, and the oxygen-regulated protein was only found in the differentiated MGc80-3 cells. CONCLUSION: The induced differentiation of carcinoma cells is accompanied by the changes of nuclear matrix proteins. Further characterization of those proteins will show the mechanism of cellular proliferation and differentiation, as well as cancer differentiation.

Adenocarcinoma, Mucinous↗
PubMed1986

Receptor binding in the rat liver nuclear matrix.

3H-Dexamethasone (Dex)-receptor complexes prepared from the rat liver cytosol efficiently bound to the nuclear matrix from the same tissue. The binding was increased with the concentration of the 3H-Dex-receptor complex added and reached a maximum plateau. However, when the partially purified 3H-Dex-receptor complex was used, saturation of the binding sites in the nuclear matrix was not observed in the range of concentration of 3H-Dex-receptor complex used. Therefore, it was considered that the apparent saturability observed in the binding of the unpurified receptor complexes is caused by the translocation inhibitor(s) in the cytosol. When the binding capacity was expressed on the basis of unit weight of DNA, the nuclear matrix exhibited 20 times more of that of the unfractionated nuclei. However, no line of evidence of enrichment of the binding sites in the DNA isolated from the nuclear matrix was observed. These observations show that the role of the nuclear matrix in the action of glucocorticoid is quite uncertain.

Animals↗
PubMed1991

Preferential binding of the carcinogen benzo[a]pyrene to proteins of the nuclear matrix.

Rat liver nuclei or hepatocytes were incubated with the procarcinogen benzo[a]pyrene (B[a]P) and its ultimate carcinogen, anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). When nuclei were fractionated by mild micrococcal nuclease digestion into different chromatin regions to determine the distribution of covalent binding to proteins, there was a much higher level of B[a]P bound to proteins of the non-released fraction than to those of released mono- and oligonucleosomes. When non-released material was further fractionated with 2 M NaCl, the highest level of B[a]P binding was found in the proteins of the salt-insoluble fraction. Electrophoretic analysis of [3H]B[a]P-modified nuclear proteins revealed radioactive species migrating in the regions of histones H1 and H3, high mobility group (HMG) proteins 1 and 2, and various high mol. wt non-histone proteins. The non-released fraction contained prominent B[a]P-modified species migrating in the position of the lamins, major components of the nuclear matrix. To confirm B[a]P modification of nuclear matrix proteins, following exposure to B[a]P or BPDE, nuclei were fractionated by a different procedure into an active chromatin fraction, a bulk chromatin fraction, a high-salt-extracted chromatin fraction and a nuclear matrix fraction. Proteins of the nuclear matrix bound consistently more B[a]P metabolites than those of bulk chromatin. This was true following exposure to B[a]P or both low and high concentrations of BPDE, in contrast to previous data on damage to nuclear matrix DNA. Proteins of active chromatin bound more carcinogen than bulk chromatin proteins at low concentrations of BPDE, but less than bulk chromatin at higher concentrations, in parallel with previous data on DNA damage in active chromatin. The potential significance of B[a]P binding to nuclear matrix proteins is discussed.

Animals↗
PubMed1997

Altered nuclear matrix protein profiles in oncogene-transformed mouse fibroblasts exhibiting high metastatic potential.

The nuclear matrix provides the structural support of the nucleus and is involved in various cellular functions of the nucleus. Nuclear matrix proteins, which are both tissue and cell type specific, are altered with transformation and state of differentiation. Here, nuclear matrix protein profiles of oncogene-transformed mouse fibroblasts with various degrees of metastatic activity were analyzed using two-dimensional gel electrophoresis. This study shows that as the metastatic potential increases, similar nuclear matrix protein profiles are associated with each increase regardless of transformation agent.

3T3 Cells↗
PubMed2000

C/EBPalpha and C/EBPbeta are persistently associated with the rat liver nuclear matrix throughout development and the acute phase response.

The partitioning of C/EBPalpha and C/EBPbeta on the nuclear matrix structure was examined during the different transcriptional activities accompanying liver development and the acute phase (AP) response. The presence of C/EBPalpha and C/EBPbeta was established on the nuclear matrix. Their relative concentrations on the matrix always reflected the developmental stage- and AP-related fluctuations observed in the nuclear extract. Thus, they progressively increased as development proceeded, whereas during the AP response, C/EBPalpha decreased and C/EBPbeta increased. In addition, the levels of both transcription factors were always notably higher in the nuclear matrix than in the extracts. We conclude that the observed changes and overall enrichment of the nuclear matrix with regulatory proteins is a reflection of the importance of such interactions for the in vivo functioning of C/EBP proteins.

Acute-Phase Reaction↗
PubMed2000

The analysis of the poly(ADPR) polymerase mode of action in rat testis nuclear fractions defines a specific poly(ADP-ribosyl)ation system associated with the nuclear matrix.

The poly(ADP-ribosyl)ation system, associated with different nuclear fractions of rat testis, has been analyzed for both pADPR and pADPR acceptor proteins. The DNase I sensitive and resistant chromatin contain 35% and 40%, respectively, of the total pADPR synthesized in intact nuclei incubated with [32P]NAD. Moreover, the residual 25% were estimated to be associated with the nuclear matrix. Three different classes of pADPR are present in the nuclei. The longest and branched ADPribose polymers modify proteins present in the DNase I resistant (2 M NaCl extractable) chromatin and in the nuclear matrix, whereas polymers of> 20 residues interact with the components of the DNase I sensitive chromatin and oligomers of 6 ADPribose residues are bound specifically to the acid-soluble chromosomal proteins, present in isolated nuclear matrix. The main pADPR acceptor protein in all the nuclear fractions is represented by the PARP itself (auto-modification reaction). The hetero-modification reaction occurs mostly on histone H1 and core histones, that have been found associated to DNase I sensitive and resistant chromatin, respectively. Moreover, an oligo(ADP-ribosyl)ation occurs on core histones tightly-bound to the matrix associated regions (MARs) of chromatin loops.

Animals↗
PubMed1992

Detection of nuclear matrix proteins in serum from cancer patients.

Morphological characteristics of the cell nucleus have long been used by pathologists in the clinical diagnosis of cancer. The nuclear matrix of the cell, the structure that serves to organize the chromatin within the nucleus, is known to reflect these morphological characteristics with regard to cell and cancer type. Monoclonal antibodies were developed to extracted nuclear matrix proteins. These antibodies were used in two-site immunometric assays to detect soluble nuclear matrix proteins in the supernatants of two dying cell lines and 15 tumor tissues. Furthermore, nuclear matrix proteins were detected at elevated levels in the sera of cancer patients compared with normal patient sera. In one assay, 63.2% of cancer sera read above 95% of normal sera, and in another assay, 73.7% of cancer sera read above 95% of the normal sera. With the development of monoclonal antibodies with greater cancer specificity, the detection of circulating nuclear matrix proteins may become an important clinical tool in the diagnosis and monitoring of cancer.

Animals↗
PubMed1998

Chromatin, nuclear matrix and the cytoskeleton: role of cell structure in neoplastic transformation (review).

Aberrant nuclear and cellular structures are hallmarks of malignant transformation. Thus it is not surprising that the three-dimensional structure of the cell both affects and is affected by changes in gene expression. Here we review the role of the cytoskeleton, nuclear matrix, and chromatin structure in the genesis of cancer. The shape of a cell is governed by a dynamic tissue matrix, which includes extracellular matrix, cytoskeleton and nuclear matrix. Mechanical and chemical signals are transmitted to the nucleus, resulting in alterations in the three-dimensional chromatin organization of genes. The signal transduction pathways affect histone modifications, such as acetylation and phosphorylation, resulting in a relaxed chromatin structure observed in oncogene-transformed cells.

Animals↗
PubMed2002

Visualization of transcription-dependent association of imprinted genes with the nuclear matrix.

Genomic imprinting is characterized by allele-specific gene expression as a biological phenomenon. To analyze the participation of the nuclear matrix in the expression of imprinted genes, we first examined the allelic expression state of genes by simultaneously visualizing their primary transcripts and the gene sequences in individual cell nuclei using fluorescence in situ hybridization (FISH). We confirmed that each imprinted gene, SNRPN and UBE3A in human lymphocytes and Igf2 and H19 in mouse embryonic fibroblasts, mainly expressed from one allele, although some nuclei showed biallelic expression. We next visualized the gene sequences on the nuclear matrix by FISH with a tyramide signal amplification technique. Interestingly, we predominantly observed one DNA signal of imprinted genes on the nuclear matrix preparation, closely correlated with their expression patterns. Using patient cells, we confirmed that both the transcription and the binding to the nuclear matrix of the SNRPN gene occurred at the paternal allele. Our results suggest that the nuclear matrix plays an important role in gene expression, including imprinted genes, and that the FISH technique used here allows us to visualize the behaviors of genes at an individual cell level.

Alleles↗
PubMed1983

The nuclear matrix of the prostate contains acceptor sites for androgen receptors.

In cell-free binding experiments, androgen receptors of rat ventral prostate cytosol bound with high affinity (Kd = 10(-10) M) to a saturable number of sites (acceptors) associated with the nuclear matrix of the prostate. This binding was dependent on the presence of an activated androgen-receptor complex. In addition, the binding was tissue-specific, since liver nuclear matrix, in contrast, contained only 15-20% as many acceptors for androgen receptors as the prostate nuclear matrix. The prostate nuclear matrix contained approximately 75% of the number of total nuclear acceptor sites. Matrix-associated acceptor sites appear to be associated with the internal RNA-protein network of the nuclear matrix since the peripheral lamina component of the matrix bound only 30% as many receptors as the intact nuclear matrix.

Animals↗
PubMed1998

A study on the relationship between antisense EGFR cDNA fragments and nuclear matrix proteins in glioblastoma cells.

The association of antisense epidermal growth factor receptor (EGFR) cDNA fragments with nuclear matrix from EGFR-antisense transfected glioblastoma cell lines U343 and U87 was investigated. A 1015 bp DNA fragment (primer I-II) was amplified in both genomic DNA and nuclear matrix-associated DNA (NM DNA) from EGFR-antisense transfected glioblastoma cell lines U343E and U87E. Two different DNA fragments (940 bp and 110 bp) were amplified by primer I-III in both genomic DNA and NM DNA of U343E, while one 110 bp PCR product was shown with the same primer in both genomic DNA and NM DNA of U87E only. After EGFR-antisense transfection, the binding property of the 110 bp DNA fragment (primer IV-V) to nuclear matrix was not affected. Southwestern blotting demonstrated the presence of antisense EGFR cDNA binding nuclear matrix proteins. Our findings demonstrate that not only EGFR DNA is associated with nuclear matrix, but the transfected antisense EGFR cDNA also binds to nuclear matrix proteins. The nuclear matrix is most likely involved in the replication and transcription of antisense EGFR cDNA or hybridisation with sense mRNA in vitro.

Brain Neoplasms↗
PubMed1992

The role of primer recognition proteins in DNA replication: association with nuclear matrix in HeLa cells.

Primer recognition proteins (PRP) enable DNA polymerase alpha to utilize efficiently DNA substrates with low primer to template ratios. We have previously identified the protein-tyrosine kinase substrate annexin II, and the glycolytic enzyme 3-phosphoglycerate kinase as components of PRP. As a step towards elucidation of the role of PRP in the process of DNA replication, we have investigated the subcellular distribution and specific association of these proteins with the nuclear matrix in HeLa cells. Nuclear extracts prepared from HeLa cells in S phase contain the enzymatic activity of 3-phosphoglycerate kinase (PGK) and phospholipase A2 inhibitory activity of annexin II. Monomer annexin II is approximately equally distributed between the nuclear and cytoplasmic fractions, while a majority of PGK is in the cytoplasm. Immunoblot analyses reveal the presence of these two proteins in nuclei, specifically associated with the nuclear matrix. This is further confirmed by observation of the presence of annexin II and PGK in isolated nuclear matrices by immunoelectron microscopy. The phospholipase A2 inhibitory activity of annexin II colocalizes with the nuclear matrix-bound annexin II. A related protein, annexin I, is not detectable in the nuclear extracts and nuclear matrix. A slower-migrating (perhaps modified) form of annexin II is found to be associated with the nuclear matrix. Attempts to dissociate PGK and annexin II from the nuclear matrix with octyl-beta-glucoside, high salt or metal ion chelators were unsuccessful, suggesting that the interaction is very strong.

Annexins↗
PubMed1984

Antibodies to the most tightly bound proteins in eukaryotic DNA. Formation of immuno-complexes with 'nuclear matrix' components.

Chromosomal DNA is associated with polypeptides covalently bound to internal DNA ends. Since these polypeptides can only be released from chromosomal DNA by enzymes or other agents hydrolysing phosphodiester bonds they were termed 'the most tightly bound' (MTB) polypeptides in DNA. Antibodies developed against the MTB polypeptides are shown to form immunocomplexes with major 'nuclear matrix' polypeptides as well as with polypeptides which are still associated with 'nuclear matrix' DNA isolated by means of SDS/proteinase K and phenol. Immuno-complex formation is revealed by immunoblotting and by indirect immunofluorescence. Thus, since MTB polypeptides, major 'nuclear matrix' polypeptides and 'nuclear matrix' DNA-associated polypeptides share common antigenic sites they can be considered to be identical or at least closely related. This suggests that a fraction of distinct 'nuclear matrix' polypeptides is either transiently or permanently linked to DNA by covalent bonds. Consistently, isolated eukaryotic 'bulk' DNA is inevitably associated with residual 'nuclear matrix' polypeptides.

Animals↗
PubMed1996

Unique nuclear matrix protein alterations in head and neck squamous cell carcinomas: intermediate biomarker candidates.

The progression of normal squamous epithelium to a malignant metastatic phenotype may depend on cellular genetic events and the failure of host mechanisms. Intermediate biomarkers are needed to more effectively identify and quantify malignant progression and develop the potential for specific treatments and prevention strategies. The nuclear matrix is the RNA-protein scaffold of the nucleus, which controls in part nuclear shape, DNA organization, and DNA function. Nuclear matrix proteins in all previously studied cell types show a common set of nuclear matrix proteins and a subset of tissue- and cell type-specific proteins. In every system studied to date, the nuclear matrix has been demonstrated to undergo quantifiable alterations in its protein composition with transformation to the malignant phenotype. The loss and gain of nuclear matrix proteins are being investigated as biomarkers for malignant transformation in breast, colon, and prostate carcinoma. We have investigated nuclear matrix protein composition in laryngeal and oral cavity primary squamous cell tumors and metastatic cervical lymph nodes. Laryngeal carcinoma demonstrated the gain of two specific nuclear matrix proteins in comparison with noncancerous squamous epithelium. Squamous cell carcinoma matrixes demonstrate greater heterogeneity than do previously studied adenocarcinoma matrixes, and yet they display specific matrix proteins that may represent important potential biomarkers.

Adult↗
PubMedDate not supplied

Alteration of nuclear matrix protein composition of neuroblastoma cells after arsenic trioxide treatment.

The aims of the present study were to assess the effects of arsenic trioxide on the nuclear matrix protein profiles of mouse neuroblastoma cells. Arsenic trioxide induces apoptosis of acute promyelocytic leukemia cells. Our results demonstrated that 2 microM As2O3 could significantly inhibit the growth of Neuro-2a cells. As early as 24 hours after As2O3 treatment, we began to observe the alteration of nuclear matrix proteins and apoptosis in tumor cells by TUNEL assay but not by DNA ladder. An increase expression of Hsc in nuclear matrix proteins of 2 microM As2O3 treated cells was also noted. Our results also showed that before a mass range of apoptosis occurred, the composition of nuclear matrix proteins had altered. Hence the alteration of nuclear matrix proteins, such as increased expression of Hsc, may be a sensitive indicator for the detection of early apoptosis.

Animals↗
PubMed1999

Dynamic redistribution of nuclear matrix proteins by adenovirus infection.

We analyzed the redistribution of nuclear proteins, PML protein, Ku70/Ku80, a putative spliceosome associated protein, pNMM102 and a nucleolar proliferating antigen, p120 after adenovirus 5 (Ad5) infection using immunofluorescent staining. These proteins remained after in situ fractionation. PML was located at irregular bars 6 h after infection from fine dots of uninfected cells. Distribution pattern of PML was not changed throughout the course of infection. Internal nuclear matrix network composed of Ku protein became much coarser in interphase cells at 12 h after infection. Ku protein was clumped at 18 h after infection, where EIA protein was colocalized. Speckles and interconnecting fibrils recognized by monoclonal antibody NMM102 disappeared early after infection, and reappeared at 18 h after infection in various patterns. The number and staining intensity of p120 containing domains increased markedly in early replication phase, and their shape became irregular with a few fine dots. A few Ad5 infected cells revealed diffuse nucleoplasmic as well as nucleolar p120 in late replication phase. Redistribution of four different nuclear matrix proteins by Ad5 infection indicates that the nuclear matrix is dynamically involved in gene expression.

Adenoviridae Infections↗