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PubMed2001

[Screening methods in the detection of bladder cancer: comparison of nuclear matrix protein-22, bladder tumor antigen and cytological examinations].

We evaluated the utility of urinary parameters (Nuclear Matrix Protein-22: NMP-22, Bladder Tumor Antigen: BTA, and cytological examinations) for the diagnosis or post-therapeutic monitoring of bladder cancer. Thirty one tumor-bearing cases including 19 fresh cases and 40 tumor-free cases, were subjects of this study. Using identical voided urine samples, NMP-22, BTA and urinary cytology were examined. The mean values of NMP-22 (cut-off value is 12 U/ml) was 100.5 +/- 26.5 U/ml in the tumor-bearing group and 21.9 +/- 7.8 U/ml in the tumor-free group (p < 0.05): Sensitivity was 74.2%, and specificity was 67.5%. Sensitivity of BTA was 58.1%, and specificity was 97.5%. Only five cases were judged positive by urinary cytology: 16.1% in sensitivity and 100% in specificity. Thus, NMP-22 and BTA were more sensitive than urinary cytology. In conclusion, the new urinary parameters, NMP-22 and BTA, would be less invasive and useful as tumor markers of bladder cancer. NMP-22 seems suitable for screening before the diagnosis and BTA for the post-therapeutic follow-up study.

Adult↗
PubMed1982

Composition and DNA-binding properties of the nuclear matrix proteins from mammalian cell nuclei.

A rapidly sedimenting DNA-protein complex was isolated from nuclear lysates in 2 M NaCl and characterized with regard to its polypeptide composition and the DNA-binding properties of the purified proteins. The complex consists of the nuclear matrix with attached DNA. Electrophoresis in SDS-polyacrylamide gels revealed two major and five minor polypeptide bands, mainly in the 60 to 75 kDa molecular weight region. The DNA-matrix complex dissociated into free DNA and proteins in the presence of 2 M NaCl and 5 M urea. The proteins could be purified by chromatography on hydroxyapatite and showed a strong tendency to reassociate at 0.15 M NaCl concentration in the absence of urea. DNA was bound to the reassociated proteins at 0.15 M NaCl concentration. Part of the DNA-protein complex was stable at 1 M NaCl concentration. The binding appeared to be random with regard to the DNA sequence.

Animals↗
PubMed2000

Ca(2+)/calmodulin-dependent protein kinase IV is expressed in spermatids and targeted to chromatin and the nuclear matrix.

Ca(2+)/calmodulin-dependent protein kinase IV and calspermin are two proteins encoded by the Camk4 gene. Both are highly expressed in the testis, where in situ hybridization studies in rat testes have demonstrated that CaMKIV mRNA is localized to pachytene spermatocytes, while calspermin mRNA is restricted to spermatids. We have examined the expression patterns of both CaMKIV and calspermin in mouse testis and unexpectedly find that CaMKIV is expressed in spermatogonia and spermatids but excluded from spermatocytes, while calspermin is found only in spermatids. CaMKIV and calspermin expression in the testis are stage-dependent and appear to be coordinately regulated. In germ cells, we find that CaMKIV is associated with the chromatin. We further demonstrate that a fraction of CaMKIV in spermatids is hyperphosphorylated and specifically localized to the nuclear matrix. These novel findings may implicate CaMKIV in chromatin remodeling during nuclear condensation of spermatids.

Animals↗
PubMed1996

Parathyroid hormone regulates the expression of rat osteoblast and osteosarcoma nuclear matrix proteins.

Parathyroid hormone (PTH) alters osteoblast morphology. How these changes in cell shape modify nuclear structure and ultimately gene expression is not known. Chronic exposure to rat PTH (1-34) [10 nM] attenuated the expression of 200, 190, and 160 kD proteins in the nuclear matrix-intermediate filament subfraction of the rat osteosarcoma cells, ROS 17/2.8 [Bidwell et al. (1994b): Endocrinology 134:1738-1744]. Here, we determined that these same PTH-responsive proteins were expressed in rat metaphyseal osteoblasts. We identified the 200 kD protein as a non-muscle myosin. Although the molecular weights, subcellular distribution, and half-lives of the 190 and 160 kD proteins were similar to topoisomerase II-alpha and -beta, nuclear matrix enzymes that mediate DNA topology, the 190 and 160 kD proteins did not interact with topoisomerase antibodies. Nevertheless, the expression of topoisomerase II-alpha, and NuMA, a component of the nuclear core filaments, was also regulated by PTH in the osteosarcoma cells. The 190 kD protein was selectively expressed in bone cells as it was not observed in OK opossum kidney cells, H4 hepatoma cells, or NIH3T3 cells. PTH attenuated mRNA expression of the PTH receptor in our cell preparations. These results demonstrate that PTH selectively alters the expression of osteoblast membrane, cytoskeletal, and nucleoskeletal proteins. Topoisomerase II-alpha, NuMA, and the 190 and 160 kD proteins may direct the nuclear PTH signalling pathways to the target genes and play a structural role in osteoblast gene expression.

Animals↗
PubMed1993

Homeodomain protein binding sites, inverted repeats, and nuclear matrix attachment regions along the human beta-globin gene complex.

beta-Globin genes in primates arose during evolution by duplication of an ancestral gene, and their order of arrangement along the DNA is related to their timing of expression during development. We believe that nuclear matrix anchorage sites (MARs) along the beta-globin gene complex considered to be mass binding sites for transcription protein factors, some of which are developmental stage specific and others ubiquitous, play a decisive role in cell memory by determining the developmental stage-specific expression of the genes. The AT-rich class of MARs appears to possess a significant number of ATTA and ATTTA motifs known to be mass binding sites for homeodomain proteins that determine body formation in development. MARs also appear to harbor origins of replication, to be enriched in inverted repeats (dyad symmetry motifs) and were proposed to include the DNase I hypersensitive sites of a particular gene determined at the chromatin level. This study is an attempt to finely identify MARs at the nucleotide level along the beta-globin gene complex. Searches of a contiguous stretch of about 73.3 kb of human sequences comprising and surrounding the epsilon, gamma G-, gamma A-, delta-, and beta-globin genes of the human beta-globin gene complex for homeotic protein binding sites as well as for inverted repeats has shown that these elements are clustered nonrandomly at particular sites within the beta-globin gene complex. These sites are presumed to be the AT-rich class of MARs of the beta-globin gene complex. The inverted repeats which are characteristic of origins of replication and some promoter/enhancer regions and the homeotic protein sites seem to include the DNase I hypersensitive sites of the gene complex. Indeed, dyad symmetry sequences are present close to the four DNase I HS sites in the locus control region (LCR) of the gene complex as well as in the 5' flanking regions and the large introns of the delta- and beta-globin genes. A search of the putative MAR regions of the gene complex suggests that, in addition to their enrichment in ATTA motifs, palindromes, and DNase I hypersensitive sites, these regions may comprise TG-rich motifs and potential Z-DNA as well as polypurine and polypyrimidine blocks. From the positions of palindromes and clusters of homeodomain protein sites along the complex we propose that an extended origin of replication able to initiate at several sites is present in the LCR and two others surrounding the delta- and beta-globin genes.(ABSTRACT TRUNCATED AT 400 WORDS)

Base Sequence↗
PubMed1988

Nuclear matrix proteins reflect cell type of origin in cultured human cells.

The low abundance proteins of the nuclear matrix (NM) were separated from the intermediate filament (IF) proteins and analyzed by two-dimensional gel electrophoresis. Three human breast carcinoma lines had virtually identical patterns of 37 NM proteins. In contrast, cell lines derived from diverse tissues had qualitatively different NM protein patterns. Together, the five cell types examined here had a total of 205 distinguishable NM proteins with 125 of these proteins unique to a single cell type. The remaining NM proteins were shared among cell types to different degrees. Polyclonal antisera, obtained by immunization with total NM proteins as antigens, preferentially stained the nuclear interior and not the exterior IF. These observations suggest that the NM proteins, localized to the interior of the nucleus, vary in a cell-type-specific manner.

Breast Neoplasms↗
PubMed1999

Localization of the Bloom syndrome helicase to punctate nuclear structures and the nuclear matrix and regulation during the cell cycle: comparison with the Werner's syndrome helicase.

The Bloom (BLM) and Werner's (WRN) syndrome proteins may regulate recombination and DNA repair. Using a novel polyclonal antibody to human BLM, we detected the 170-kda BLM antigen in wild-type but not Bloom syndrome cells. BLM was localized to punctate nuclear structures. The level of BLM but not WRN was 3.6 fold-higher in G(1)/S-synchronized fibroblasts than in G(0)-synchronized fibroblasts. BLM-positive cells invariably expressed topoisomerase IIalpha, whereas topoisomerase IIbeta was expressed constitutively. Transfections of BLM deletion mutants demonstrated that the C-terminal domain of BLM mediated nuclear entry and the central helicase domain was necessary for producing the punctate pattern. By subcellular fractionation, BLM was found primarily in high-salt extracts of the nucleoplasm and the nuclear matrix and was enriched in G(1)/S-synchronized cells compared with G(0)-synchronized cells. There was no interaction between BLM and WRN or topoisomerases IIalpha and IIbeta in fibroblasts. These results demonstrate that BLM is targeted to specific nuclear structures and that its expression is enhanced during cell growth. The known nucleolar localization of WRN, its invariant expression during the cell cycle, and the lack of interaction between BLM and WRN suggest distinct roles for BLM and WRN in processes such as DNA repair and recombination.

Adenosine Triphosphatases↗
PubMed1999

Nuclear matrix targeting of the protein kinase CK2 signal as a common downstream response to androgen or growth factor stimulation of prostate cancer cells.

Protein kinase CK2, a messenger-independent serine/threonine kinase, has been implicated in cell growth. Androgenic stimulus in rat prostate modulates its association with nuclear matrix (NM) and chromatin. Because the growth of human prostate carcinoma cells is influenced by androgens and/or growth factors, we determined the nature of CK2 signaling in the NM in response to androgen and growth factor stimuli. Androgen-sensitive LNCaP and androgen-insensitive PC-3 cells were cultured in media to regulate their growth in the presence of 5alpha-dihydrotestosterone (5alpha-DHT) or growth factors (epidermal growth factor, keratinocyte growth factor, and transforming growth factor alpha). The activity of CK2 was measured in the cytosolic and NM fractions isolated from these cells after treatment with growth stimuli. The changes in CK2 in various fractions were also confirmed by immunoblotting with a specific antibody. LNCaP cells responded to both 5alpha-DHT and growth factors for growth. The presence of these agents in the culture medium evoked a translocation of CK2 to the NM from the cytosol. The PC-3 cells did not respond to 5alpha-DHT for growth but did respond to growth factors. Under these conditions, there was also a translocation of CK2 to the NM concomitant with a decrease in the cytosolic fraction. These results suggest that CK2 translocation to the NM occurs in response to various growth stimuli in cells in culture. Thus, CK2 is a common downstream signal transducer in response to diverse growth stimuli that may relate to the pathobiology of prostate cancer cells.

Adenocarcinoma↗
PubMed2001

The nuclear matrix and chromosomal DNA loops: is their any correlation between partitioning of the genome into loops and functional domains?

In this paper we are presenting a critical analysis of the results of experiments aimed to elucidate the principles of the eukaryotic genome structural-functional organization. Although the DNA loops attached to the nuclear matrix (chromosomal scaffold) are frequently considered as independent functional domains, this supposition lack experimental proofs as far as the transcriptional domains are concerned. On the contrary, many observations indicate that organization of chromosomal DNA into loops is directly related to the replicon structure of the genome.

Animals↗
PubMed1986

Nuclear matrix proteins are crosslinked to transcriptionally active gene sequences by ionizing radiation.

Unirradiated, exponentially growing Chinese hamster cells contain a low level (less than 5%) of their DNA firmly bound to protein, as measured by a filter-binding assay. That fraction of DNA is highly enriched in sequences which hybridize to poly(A+)RNA or ribosomal RNA. After 60 Gy gamma irradiation, the additional crosslinked DNA is also enriched in transcriptionally active sequences compared to bulk DNA, while DNA crosslinked by uv radiation has a frequency of active sequences which is no higher than the bulk DNA. DNA crosslinked to protein by gamma radiation but not by uv is largely released during a 4-h postirradiation incubation. The DNA which remains bound to protein during that period becomes depleted in active sequences; this is followed by an apparent restoration of the active gene-enriched protein complex found in unirradiated cells. When nuclear matrix-associated DNA was isolated free of the majority ("loop") DNA, an enrichment for active DNA sequences was found in the matrix-associated DNA, and the frequency of DNA-protein crosslinks was found to be 10- to 16-fold greater in the matrix fraction. Gel electrophoretic analysis of the crosslinking proteins identifies them as subset of proteins of the nuclear matrix. These data are consistent with known properties of the nuclear matrix and suggest that chromatin structure plays an important role in the formation and repair of gamma-radiation-induced DNA lesions.

Animals↗
PubMed1998

Nuclear matrix protein, tumor necrosis factor-alpha, and nitrite/nitrate levels in patients with multiple organ dysfunction syndrome.

Nuclear matrix protein (NMP), an indicator of apoptosis, was analyzed in patients with multiple organ dysfunction syndrome (MODS). Blood levels of tumor necrosis factor-alpha (TNF-alpha) and nitrite/nitrate (NOx) were also measured in these patients to determine the involvement of these factors in the production of NMP. Forty-six patients with MODS were studied, 21 (45.7%) of whom died. NMP and TNF-alpha were measured by enzyme-linked immunosorbent assay (ELISA). NOx was measured by the Griess's method. Marshall's multiple organ dysfunction score (MOD score) was used as an indicator of organ failure. The severity of organ failure was assessed by use of the acute physiology and chronic health evaluation II score (APACHE II score). The number of organs that failed was found to be significantly correlated with the NMP level. The NMP level was also correlated significantly with MOD score and APACHE II score, as well as with TNF-alpha and NOx levels. NMP and NOx levels in the group that died significantly exceeded those in the surviving group. Results suggest that apoptosis can occur in the presence of MODS, and that its extent increases as the number of failing organs increases. The results also suggest that TNF-alpha and NO are involved in the induction of apoptosis.

Adolescent↗
PubMed2005

Urinary nuclear matrix protein 22 for diagnosis of renal cell carcinoma.

OBJECTIVE: To determine the incidence of positive urinary nuclear matrix protein 22 (NMP22) values, which are currently used to detect transitional cell carcinoma of the bladder, in renal cell carcinoma (RCC). MATERIAL AND METHODS: Urinary NMP22 values were determined preoperatively in 41 patients in whom a solid renal mass had been detected using CT and who were scheduled for radical nephrectomy; 38 of these patients were diagnosed with RCC. Two patients had xanthogranulomatous pyelonephritis and one had metastasis of a small cell adenocarcinoma to the kidney; these patients were excluded from the study. A total of 30 patients with kidney stones and simple renal cysts were used as controls. RESULTS: The urinary NMP22 values of the RCC patients were significantly higher than those of the controls. Of the 38 patients with RCC, 23 (60.5%) had positive urinary NMP22 values > or =10 U/ml. There were four measurements above this cut-off level in the control group. Urinary NMP22 values increased with an increase in pathologic tumor stage, but the correlation was not statistically significant. There was no correlation between grade and urinary NMP22 or between tumor burden and urinary NMP22. CONCLUSIONS: The urinary NMP22 test may help to diagnose RCC and may also result in an increase in the incidental discovery of RCC. As elevated urinary NMP22 levels have also been found to occur in RCC, patients with suspected bladder cancer and positive urinary NMP22 levels should be more broadly evaluated. Specific NMP assays for renal tumor cells may increase the utility of the test for RCC.

Biomarkers, Tumor↗
PubMed1990

The synthesis of influenza virus negative-strand RNA takes place in insoluble complexes present in the nuclear matrix fraction.

The replication of influenza virus RNA in vitro has been studied by cell fractionation of MDCK-infected cells and characterization of in vitro synthesized RNA. Analysis of the RNA product polarity by liquid hybridization to excess single-stranded DNA probes shows that only the RNP complexes present in the nuclear matrix fraction are able to synthesize negative-polarity RNA. This RNA product has been characterized as authentic vRNA by size analysis, RNase-protection by unlabelled, positive-polarity riboprobes and T1-fingerprinting. Priming the in vitro reaction with ApG stimulates preferentially the synthesis of positive-polarity RNA, while ApGpU stimulates both positive and negative-polarity RNA synthesis.

Animals↗
PubMed1987

Nuclear matrix and chromosome scaffold preparations of in vitro cultured bovine liver cells have two proteins in common.

Nuclear matrices and chromosome scaffolds of in vitro cultured bovine liver cells were prepared under conditions that preserve the specific binding of the DNA. Protein compositions were analysed by electrophoresis and peptide mapping. Two slightly acidic polypeptides of apparent molecular masses 47 and 53 kDa were present in nuclear matrix as well as chromosome scaffold preparations. The corresponding matrix and scaffold proteins had identical peptide maps. Their putative function in the spatial organization of the DNA during the cell cycle is considered.

Animals↗
PubMed1983

Investigations of the possible functions for glycosylation in the high mobility group proteins. Evidence for a role in nuclear matrix association.

Techniques are described for selectively removing the carbohydrate moieties from the high mobility group (HMG) 14 and 17 proteins of Friend erythroleukemia and calf thymocyte cells without causing degradation of these nonhistone proteins. Investigations were therefore undertaken to investigate the possible significance of this secondary biochemical modification by comparing the activity of the HMGs with and without their glycosyl side chains in various functional assays of the proteins. For example, these HMGs have been found to be equally effective in the partial inhibition of the histone deacetylase enzymes of mammalian cell nuclei whether or not they contain covalently bound carbohydrate residues. We also investigated the possibility that the glycosyl modifications might be involved in the reported ability of these HMGs to specifically cause reconstitution of the DNase I-sensitive structure of "active" genes in salt-depleted chromatin. Unexpectedly, in experiments with both the active beta-globin gene of Friend cells and the total complement of active genes in these same mouse cells (which can be preferentially labeled by nuclear nick translation) we have been unable, using purified HMG 14 and 17 preparations, to reconstitute the active DNase I structure of genes in salt-depleted chromatin preparations. Therefore, the possible role, if any, played by HMG glycosylation in such reconstitution experiments remains unknown. However, in the course of these experiments we did find that HMG 14 and 17 proteins covalently linked to carbohydrate side chains bind preferentially to the nuclear protein matrix of mammalian cells. Furthermore, this association appears to be mediated through the glycosyl side chains since enzymatic removal of these modifications from the HMGs greatly reduced their binding to the nuclear matrix. Since numerous workers have implicated the nuclear matrix as the site of both RNA transcription and DNA replication in eukaryotic cells, the finding of HMG association with this nuclear structure may have significance for our understanding of the overall architectural organization of the active domains of chromatin in cells.

Animals↗
PubMed1997

Transport of protein kinase C isoforms to the nucleus of PC12 cells by nerve growth factor: association of atypical zeta-PKC with the nuclear matrix.

In an effort to understand the role of protein kinase C (PKC) in nerve growth factor-induced differentiation, we studied the expression of PKC using isoform-specific antibodies. Western blot analysis on whole cell lysates showed that alpha,beta,gamma,epsilon,zeta, iota/lambda and mu were expressed in PC12 cells, except for theta which was absent. In nuclei obtained from control PC12 cells, small amounts of delta, epsilon, iota/lambda and zeta were detected. A computer-assisted search algorithm was used to search for the presence of bipartite nuclear targeting motifs. In classical PKC isoforms alpha,beta,gamma, two bipartite motifs were present, while atypical iota/lambda and zeta-PKC displayed one motif, whereas novel PKC isoforms did not exhibit any bipartite motif structure. Treatment of cells with differentiating doses of nerve growth factor (NGF) resulted in changes of differential magnitude for all of the nuclear PKC isoforms in response to NGF. However, little change in gamma-PKC was observed in response to NGF. This analysis indicated that other factors may contribute to transport of PKC into the nucleus, in addition to the bipartite motif itself. Atypical zeta-PKC is required for NGF-induced neurite outgrowth of PC12 cells (Coleman and Wooten: J Mol Neurosci 5:39-57, 1994). Increases in nuclear zeta-PKC were NGF dose-dependant with a concomitant decrease in cytoplasmic immunoreactivity. The localization of zeta-PKC was investigated by means of immunoelectron microscopy which revealed the localization of this isoform within the inner nuclear matrix bound to chromatin. Taken together, these findings suggest that zeta-PKC may be involved in the regulation of nuclear processes.

Animals↗
PubMedDate not supplied

Clinical implications of measurement of serum nuclear matrix protein levels in patients with liver disease.

BACKGROUND/AIMS: Serum aminotransferase, a sensitive marker of hepatocellular damage, often poorly correlates with the severity of damage. Serum nuclear matrix protein (NMP), a structural protein released from dead cell nuclei, is investigated as a candidate marker of organ damage in liver disease. METHODOLOGY: Serum NMP and aminotransferase levels of 134 patients with various liver diseases and 26 healthy individuals were examined. RESULTS: Patients with chronic viral hepatitis showed slightly higher NMP levels (17.8 U/mL; 95% CI 15.0-20.5 U/mL) than those of healthy individuals (6.05 U/mL; 95% CI 4.82-7.27 U/mL). Their NMP values had no correlation with aminotransferase levels. NMP levels were similar irrespective of liver disease progression, whereas aminotransferase values decreased in parallel with progression. Patients with autoimmune hepatitis or primary biliary cirrhosis who were under an appropriate treatment as well as individuals with fatty liver showed no elevation of serum NMP levels. Patients with acute viral hepatitis showed very high NMP levels (38.8 U/mL; 95%CI 27.6-50.0 U/mL) that correlated with serum aminotransferase levels in their sera. CONCLUSIONS: In chronic liver diseases, the serum NMP level elevates to various degrees independent from the degree of aminotransferase elevation. Serum NMP, putatively representing the number of dead cells, is a candidate as an indicator of organ damage severity in liver disease.

Adult↗
PubMed2000

Nuclear matrix proteins are carried within peripheral material of mitotic chromosomes.

Immunofluorescent analysis has shown that autoimmune sera M-222 and M-260 are bound to interphase nuclei and mitotic chromosomes of the pig embryo kidney cell culture. The fluorescent stain is diffuse in nuclei and forms a thin fluorescent area around each nucleolus, whereas the nucleolar cores are unstained. The periphery of each mitotic chromosome is stained distinctly. After removal of histones and DNA by the cell treatment with 2 M NaCl and DNase I, the Hoechst 33258 staining of nuclei and chromosomes disappears completely, whereas the pattern of staining with antibodies is not changed as compared with normal cells. Electron microscopy revealed in interphase nuclei after such treatment only lamina, residual nucleoli, and the intranuclear matrix network, and antibodies are bound just to these elements. Molecular mass of proteins bound to these antibodies was determined by immunoblotting. Serum M-260 contained antibodies to a single 65 kDa polypeptide, whereas antibodies to two polypeptides of 47 and 65 kDa were found in M-222. After chromatin removal and revealing nuclear protein matrix, M-222 binds only to 65 kDa polypeptides. Thus, peripheral chromosomal material is involved in transfer of the nuclear matrix polypeptide to daughter nuclei during mitosis.

Animals↗