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PubMed2003

The addition of urinary urokinase-type plasminogen activator to urinary nuclear matrix protein 22 and cytology improves the detection of bladder cancer.

PURPOSE: We have previously reported that urinary urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are elevated in patients with bladder cancer. In the current study we tested the hypothesis that urinary uPA and uPAR would add to the predictive ability of urinary nuclear matrix protein 22 (NMP22) and cytology for the diagnosis of bladder cancer. MATERIALS AND METHODS: Urinary uPA, uPAR and NMP22 were measured in voided specimens obtained before cystoscopy in 229 consecutive subjects at risk for transitional cell carcinoma (TCC), of whom 122 (53%) were found to have bladder TCC. Bladder washout samples for cytology were also collected in 191 subjects. Associations with TCC were tested by logistic regression. Nonparametric ROC curves were generated and AUCs were compared. RESULTS: Urinary uPA, uPAR and NMP22 were higher in patients with TCC than in controls (p <0.001, 0.016 and <0.001, respectively), while uPA (test for trend p = 0.018) was associated with the risk of TCC after adjusting for NMP22 (p = 0.028), urinary cytology (p <0.001), age (p = 0.107) and uPAR (test for trend p = 0.756). The overall AUC for determining TCC was not different between uPA and NMP22 (0.746 and 0.714, p = 0.092). However, in the high sensitivity region of the ROC curve the AUC of uPA was larger than that of NMP22. CONCLUSIONS: Adding uPA to NMP22 and cytology improves their ability to predict bladder TCC by a statistically and prognostically substantial margin. An approach using multiple biomarkers may improve the diagnostic accuracy of voided urinary diagnostic tests.

Adult↗
PubMed2003

Comparison of the nuclear matrix protein 22 with voided urine cytology in the diagnosis of transitional cell carcinoma of the bladder.

Several urinary markers for transitional cell carcinoma have been investigated, including urine cytology, bladder tumor antigen, autocrine motility factor receptor and fibrin degradation products. Unfortunately, they have poor overall sensitivity. The United States Food and Drug Administration have recently approved nuclear matrix protein (NMP 22) for the detection of occult or rapidly recurring disease after transurethral resection of bladder tumor. The objective of the current study was to assess the sensitivity of NMP 22 for the detection of bladder carcinoma, as well as to correlate the NMP 22 values with multiplicity of tumor, tumor size, configuration, stage and grade respectively. A total of 78 patients (38 with bladder cancer) provided a urine sample which was divided into appropriate aliquots for each of urine cytology and NMP 22. Comparative results demonstrate a clear superiority of NMP 22 in bladder cancer detection (52.6% vs 31.6% sensitivity), while specificity was in favor of urine cytology (100% vs 82.5%). For superficial tumors, sensitivity was 78.5% for NMP 22 and 41.6% for cytology and for invasive cancers, sensitivity was 90% for NMP 22 and 60% for cytology. Urinary NMP 22 levels were significantly correlated with tumor grade and were significantly higher in large tumors than small tumors. NMP 22 test results showed sufficient sensitivity in comparison with urine cytology for the detection of transitional cell carcinoma. However, we do not think that it is a useful tool as a substitute for endoscopic examination for the detection and surveillance in bladder cancer.

Biomarkers, Tumor↗
PubMed1991

A 210 kDa nuclear matrix protein is a functional part of the mitotic spindle; a microinjection study using SPN monoclonal antibodies.

Six monoclonal antibodies identify a 210 kDa polypeptide which shows a cell cycle specific redistribution from the nucleus to the mitotic spindle. In interphase cells this polypeptide was localized in the nucleus and behaved during differential cell extraction as a component of the nuclear matrix. It accumulated in the centrosome region at prophase, in the pole regions of the mitotic spindle at metaphase and in crescents at the poles in anaphase, and reassociated with the nuclei as they reformed in telophase. Due to its staining pattern we call the protein the Spindle Pole-Nucleus (SPN) antigen. The localization of SPN antigen during mitosis was dependent on the integrity of the spindle since treatment of cells with nocodazole resulted in the dispersal of SPN antigen into many small foci which acted as microtubule organizing centres when the drug was removed. The SPN antigen was present in nuclei and mitotic spindles of all human and mammalian cell lines and tissues so far tested. When microinjected into the cytoplasm or nuclei of HeLa cells, one antibody caused a block in mitosis. Total cell number remained constant or decreased slightly after 24 h. At this time, about half the cells were arrested in a prometaphase-like state and revealed aberrant spindles. Many other cells were multinucleate. These results show that the SPN antigen is a protein associated with mitotic spindle microtubules which has to function correctly for the cell to complete mitosis.

Antibodies, Monoclonal↗
PubMed2002

The role of nuclear matrix protein 22 combined with bladder tumor antigen stat test in surveillance of recurring bladder cancer.

OBJECTIVE: To investigate a non-invasive, effective and rapid mode of detecting the recurrence of bladder cancer during follow-up. METHODS: Ninety patients following transurethral resection of bladder tumor (TURBt) surgery were recruited from January 1998 to March 2000. Standard ELISA was used to determine the quantity of nuclear matrix protein (NMP-22) in urine of all bladder cancer patients during their follow-up periods. Urine bladder tumor antigen (BTA) stat test was simultaneously performed and followed by cystoscopy. RESULTS: The total positive rates of urinary NMP-22 and BTA stat test were 76.7% (33/43) and 67.4% (29/43), respectively. Comparatively, this positive rate would increase to 93.0% (40/43) when the combination of both urine NMP-22 and BTA test were adopted. CONCLUSION: Examination of NMP-22 in urine is a rapid and effective way to detect the recurrence of bladder cancer. If combined with BTA test, NMP-22 may be used as a non-invasive method in surveillance of recurring of bladder cancer, which may reduce the frequency of patients needing to undergo conventional invasive cystoscopy.

Antigens, Neoplasm↗
PubMed2003

Measurements of complement factor H-related protein (BTA-TRAK assay) and nuclear matrix protein (NMP22 assay)--useful diagnostic tools in the diagnosis of urinary bladder cancer?

Between 1997 and 2000 we investigated in a prospective study the voided urine samples of all consecutive patients undergoing cystoscopy independent from their clinical background (n = 705) with the BTA-TRAK assay (Bard Diagnostics, Redmont, USA) detecting a complement factor H-related protein (CFHrP) and the NMP22 assay (Matritech, Newton, USA) measuring a nuclear matrix protein, which is supposed to be specific for bladder cancer. The individuals were divided into three groups concerning the clinical background: 233 patients had urological diseases, 268 patients had urinary bladder cancer and 150 patients had other urological malignancies. Based on the clinical findings we compared our results with well established diagnostic methods for urinary bladder cancer such as cytology and the detection of hematuria. In addition, we investigated urine samples from 30 healthy individuals and 24 patients with urinary tract infection without performing cystoscopy. Following the recommendations of the European Group on Tumor Markers we used 95% specificity for benign urological diseases and urinary tract infections, which resulted in a sensitivity of 17% for active bladder cancer for the BTA-TRAK assay and 31% for NMP22. We compared these results with the detection of hematuria (specificity: 72%) and cytology, which had a sensitivity of 64% and 89%, respectively. Subsequently, we calculated sensitivity and specificity for the detection of relapse of the disease. Again using 95% specificity, in this case for patients with no evidence of disease (NED), in patients with recurrent disease the BTA-TRAK assay showed 8% sensitivity as compared to 12% for the NMP22 assay. Due to an insufficient specificity and sensitivity, both tests can neither be clinically useful in screening of high risk patients, nor in primary diagnosis of bladder cancer. They cannot replace neither cystoscopy nor cytology. In the follow-up care more investigations may be necessary to prove the benefit of existing diagnostic strategies for the discrimination between active and inactive bladder cancer.

Biomarkers, Tumor↗
PubMed1984

Specific internalization of estrogen and binding to nuclear matrix in isolated uterine cells.

Fractionation of rat uterine cells incubated at 22 degrees C with 0.2 nM [3H]-estradiol-17 beta (E2 beta) was performed to analyze the subcellular distribution of internalized hormone. The postnuclear supernatant of homogenates was resolved in Percoll density gradients into six major fractions defined by enzyme markers. Within 10 s, E2 beta concentrates at the density of plasma membranes and also at a more buoyant density (p = 1.052 +/- 0.001) with peak accumulation of hormone by 2 min. Thereafter, binding in the latter fraction declines concomitantly with appearance of a portion of hormone at higher densities corresponding to Golgi and lysosomes. E2 beta exhibits preferential accumulation in nuclear matrix from 5 to 60 min. Microfiltration and scanning electron microscopy of the buoyant 2-min peak fractions reveal organelles, 50-200 nm. These may represent endocytotic vesicles that serve as vehicles for nuclear transfer of hormone.

Animals↗
PubMed1987

The c-myc protein is associated with the nuclear matrix through specific metal interaction.

We have investigated the subnuclear localisation of the protein product of the c-myc oncogene. We show that, although c-myc is not present in the nuclear skeleton or matrix II fraction, it is associated with the nuclear matrix I fraction which is a complex group of proteins implicated in physiological processes within the nucleus. The interaction of the c-myc protein and the matrix I fraction is through a specific metal interaction and presumably, therefore, represents the in vivo location of this protein.

Carcinoma, Small Cell↗
PubMed2001

CHMP1 is a novel nuclear matrix protein affecting chromatin structure and cell-cycle progression.

The Polycomb-group (PcG) is a diverse set of proteins required for maintenance of gene silencing during development. In a screen for conserved partners of the PcG protein Polycomblike (Pcl), we have identified a new protein, human CHMP1 (CHromatin Modifying Protein; CHarged Multivesicular body Protein), which is encoded by an alternative open reading frame in the PRSM1 gene and is conserved in both complex and simple eukaryotes. CHMP1 contains a predicted bipartite nuclear localization signal and distributes as distinct forms to the cytoplasm and the nuclear matrix in all cell lines tested. We have constructed a stable HEK293 cell line that inducibly overexpresses CHMP1 under ecdysone control. Overexpressed CHMP1 localizes to a punctate subnuclear pattern, encapsulating regions of nuclease-resistant, condensed chromatin. These novel structures are also frequently surrounded by increased histone H3 phosphorylation and acetylation. CHMP1 can recruit a PcG protein, BMI1, to these regions of condensed chromatin and can cooperate with co-expressed vertebrate Pcl in a Xenopus embryo PcG assay; this is consistent with a role in PcG function. In combination, these observations suggest that CHMP1 plays a role in stable gene silencing within the nucleus.

Amino Acid Sequence↗
PubMed1997

The role of nuclear matrix protein 22 in the detection of persistent or recurrent transitional-cell cancer of the bladder.

Successful management of transitional-cell carcinoma of the urinary bladder is greatly dependent upon regular surveillance and early detection of persistent or recurrent carcinoma. The development of a highly sensitive urinary test for the detection of transitional-cell carcinoma of the bladder could have a dramatic impact on our ability to diagnose and monitor bladder cancer patients as well as influence the treatment outcome. The urinary level of the nuclear matrix protein, NMP22, has been found to be elevated in patients with urothelial malignancy. This has prompted the development of an immunoassay to quantitate urinary NMP22 and use it as a cancer-specific marker. We provide a summary of the studies completed with the immunoassay for urinary NMP22 as an indicator for the presence of transitional-cell carcinoma and compare the results with those obtained using other screening modalities.

Biomarkers, Tumor↗
PubMed1986

A protein-tyrosine kinase in the nuclear matrix from rat liver.

Protein kinase activity in isolated nuclei from rat liver was detected in situ after electrophoresis on SDS-polyacrylamide gel containing no exogenous protein substrate. After renaturation of polypeptides, the gel was incubated with [gamma-32P]ATP and divalent cations. Among five major protein kinase activities observed as radioactive bands by autoradiography, a protein kinase autophosphorylating on tyrosine (Mr 30,000) was identified and found to be localized in the nucleus, particularly in the nuclear matrix. The intensity of the activity band representing the level of the protein-tyrosine kinase in rat liver nuclei did not appreciably change during 3-24 h after partial hepatectomy.

Animals↗
PubMed2000

Computer prediction of sites associated with various elements of the nuclear matrix.

Attachment regions of the eukaryotic chromosomal DNA to the nuclear scaffold/matrix (S/MARs) participate in various important cellular processes. However, no obvious characteristics common for these nucleotide sequences have been revealed, except that S/MARs are non-coding sites containing putative regulatory elements and binding sites of DNA-topoisomerase II. Heterogeneity among S/MARs can be caused by a variety of biological factors. In this paper, the accuracy of two S/MARs prediction programs, MAR-Finder (Singh, Kramer and Krawetz, 1997) and ChrClass (Glazkov, Rogozin and Glazko, 1998) are compared and it is concluded that both programs can be recommended for analysis of eukaryotic genomes. However, results of their prediction should be interpreted with caution since estimation of prediction accuracy of both programs needs further analysis. Problems of S/MARs prediction are illustrated on several examples of human protein-coding genes, repeated elements and the beta-globin locus from different mammalian species. Results of our analysis suggest that the proportion of missed S/MARs is lower for ChrClass, whereas the proportion of wrong S/MARs is lower for MAR-Finder (a default set of parameters).

Animals↗
PubMed1988

The role of cytoskeleton and nuclear matrix in virus replication.

In the light of the cytoarchitecture concept, the presented review attempts to cover what is known of the involvement of cytoskeletal and nucleoskeletal elements in the replication cycle of various viruses and in cell transformation. Our knowledge on the relationship of virus replication with cell architecture has rapidly progressed during the recent years in association with studies on composition of various filaments within cells, their spatial organization and possible functions which focussed much interest on the cytoskeleton and nuclear matrix. The new results indicated that highly specialized elements for normal cell function may be coopted for virus growth. Recently, using various methodical approaches it has been possible to obtain information about the association of virus-structural proteins with cytoskeletal and nucleoskeletal elements, about the reorganization of cytoskeleton during virus replication, about the role of tubulin in transcription and RNA synthesis of negative-strand viruses, about the involvement of cytoskeletal filaments in the transport of viral proteins, virus penetration, virus assembly and release from the infected cell. The role of cytoskeleton in cell transformation and in initiation of DNA synthesis and intracellular signaling to cell proliferation has been also investigated.

Adenoviridae↗
PubMed1982

A nuclear matrix antigen HeLa and other human malignant cells.

Antisera were obtained in rabbits to preparations of dehistonized chromatin from HeLa cells. By complement fixation assays, the antisera reacted with HeLa cell chromatin but only marginally with human placenta chromatin. The complement-fixing reactivity of the antisera was inversely related to the amount of dehistonized chromatin used for immunization. Immunochemical staining of electrophoretically separated chromosomal proteins transferred to nitrocellulose sheets revealed numerous antigens in chromatin preparations from several human tumors, placenta, and normal kidney. While immunoabsorption of the antisera with placenta chromatin removed some of the immunochemical staining, many of the electrophoretically separated antigens resisted repeated immunoabsorptions. However, further comparisons revealed that only one major protein antigen (band at an approximate molecular weight of 81,000) was represented in all the assayed human tumors while being absent from human placenta or kidney. Fractionation of HeLa cells into three cytoplasmic and several nuclear fractions showed that almost all the antigens recognized by antisera to dehistonized chromatin were nuclear. The antigenic protein with an approximately molecular weight of 81,000 was found associated with the nuclear matrix fraction.

Antigens↗
PubMed1988

Catalase in guinea pig hepatocytes is localized in cytoplasm, nuclear matrix and peroxisomes.

We have compared the intracellular localization of catalase and another peroxisomal marker enzyme, alpha-hydroxy acid oxidase (HAOX), in the livers of guinea pig and rat using immunoelectron microscopy and subcellular fractionation combined with immunoblotting and enzyme activity determination. Antibodies against both enzymes were raised in rabbits and their specificities established by immunoblotting. By immunoelectron microscopy, gold particles representing antigenic sites for catalase were found in guinea pig hepatocytes not only in peroxisomes but also in the cytoplasm and the nuclear matrix. In rat liver, however, catalase was localized exclusively in peroxisomes with no cytoplasmic labeling. Moreover, in both species HAOX was found only in peroxisomes. Subcellular fractionation revealed that purified peroxisomes from both species contained comparable levels of each, catalase and HAOX activities. The total catalase activity, however, was substantially higher in guinea pig and most of this excess catalase was in the cytosolic fraction with some activity also in nuclei. In rat liver, 30 to 40% of both enzymes and in guinea pig liver 30% of HAOX were recovered in the supernatant fraction implying that the fragility of peroxisomes in both species is quite comparable. These observations establish the occurrence of extraperoxisomal catalase in guinea pig liver. The catalase in the cytoplasm and nucleus of liver parenchymal cells is most probably involved in scavenging of H2O2, protecting the cell against toxic and mutagenic effects of this noxious agent.

Animals↗
PubMed1987

Identification of protein antigens associated with the nuclear matrix and with clusters of interchromatin granules in both interphase and mitotic cells.

Monoclonal antibody 3C5 recognizes a family of protein antigens present predominantly within the nucleus of interphase cells. We have shown previously that the epitope recognized by 3C5 is phosphorylated and have concluded that the proteins defined by this antibody share a common phosphorylation site. Using a combination of immunofluorescence microscopy and immunogold labelling in conjunction with electron microscopy, we have studied the distribution of 3C5-reactive material within interphase and mitotic cells. Antibody 3C5 was found to label specific structures within the interphase nucleus that, on the basis of their characteristic granulofibrillar morphology and strong staining with bismuth, have been identified as clusters of interchromatin granules (IG clusters). Double-labelling experiments with 3C5 and monoclonal antibodies to DNA have shown that these structures contain no detectable DNA. However, by indirect immunofluorescence, we have shown that 3C5-reactive nuclear structures do label with human autoantibodies to the Sm antigen, a component of small nuclear RNP particles (snRNPs). Granulofibrillar structures that stained strongly with bismuth, and were morphologically identical to nuclear IG clusters, were observed in the cytoplasm of mitotic cells. These structures also labelled with 3C5 but not with anti-Sm antibodies. Our results suggest that IG clusters remain essentially intact through mitosis though some snRNP components are apparently lost. In situ extraction of cultured cells with Triton X-100, micrococcal nuclease and 1-2M-NaCl failed to deplete 3C5-reactive material in either interphase or mitotic cells, though some redistribution was evident. In addition, 3C5-reactive proteins were identified in nuclear matrices prepared from rat liver by high-salt extraction procedures. However, the recovery of such proteins was strongly influenced by the preparation technique employed. Our results suggest that 3C5-reactive proteins and IG clusters are anchored to, but not integral components of, salt-resistant structural elements of the interphase nucleus and the mitotic cytoplasm, presumably the nuclear matrix and the cytoskeleton, respectively.

Animals↗
PubMed2005

Nomograms including nuclear matrix protein 22 for prediction of disease recurrence and progression in patients with Ta, T1 or CIS transitional cell carcinoma of the bladder.

PURPOSE: We developed and validated nomograms that accurately predict disease recurrence and progression in patients with Ta, T1, or CIS transitional cell carcinoma (TCC) of the bladder using a large international cohort. METHODS: Univariate and multivariate logistic regression models targeted histologically confirmed disease recurrence, and focused on 2,542 patients with bladder TCC from 10 participating centers. Variables consisted of pre-cystoscopy voided urine Nuclear Matrix Protein 22 (NMP22) assay, urine cytology, age and gender. Resulting nomograms were internally validated with bootstrapping. Nomogram performance was explored graphically with Loess smoothing plots. RESULTS: Overall 957 patients had recurrent TCC. Tumor grade and stage was available for 898 patients, including 24% grade I, 43% grade II, and 33% grade III; 45% stage Ta, 32% T1 and/or CIS, and 23% T2 or greater. Bootstrap corrected predictive accuracy for any TCC recurrence was 0.842; grade III Ta/T1 or CIS was 0.869; and T2 or higher stage TCC of any grade was 0.858. Virtually perfect performance characteristics were observed for the nomograms predicting any TCC recurrence or grade III Ta/T1 or CIS. The nomogram predicting T2 or higher stage TCC overestimated the observed probability for predicted values greater than 45%. CONCLUSIONS: We developed and internally validated nomograms that incorporate urinary NMP22, cytology, age and gender to predict with high accuracy the probability of disease recurrence and progression in patients with Ta, T1, and/or CIS bladder TCC. These nomograms could provide a means for individualizing followup in patients with Ta, T1, CIS bladder TCC.

Adolescent↗
PubMed1983

94,000- and 100,000-molecular-weight simian virus 40 T-antigens are associated with the nuclear matrix in transformed and revertant mouse cells.

A small fraction of the 94,000-molecular-weight multifunctional large T-antigen of simian virus 40 was associated with the nuclear protein matrix derived from simian virus 40-transformed mouse cells. The interaction between this fraction of T-antigen and the matrix was largely or entirely independent of nuclear DNA. Similar amounts of T-antigen were retained by the nuclei of transformed and revertant cell lines. A 100,000-molecular-weight variant of T-antigen, which has been found to correlate specifically with anchorage-independent growth, was present in the nuclear protein matrix of a transformed cell line. A T-antigen-containing revertant selected for the reacquisition of a high serum requirement and an anchorage requirement for growth retained T-antigen in association with its matrix.

Animals↗
PubMed1999

Repression of the wing vein development in Drosophila by the nuclear matrix protein plexus.

The wing of Drosophila is separated into several sectors by the wing veins. Vein primordia are specified by the positional information provided by hedgehog and decapentaplegic in the wing imaginal disc and express the key regulatory gene rhomboid. One model of this process is that boundaries of gene expression regulated by hedgehog or decapentaplegic provide reference points where rhomboid transcription is activated. We present an analysis of the gene plexus, whose loss of function causes an excess vein phenotype. Molecular cloning revealed that plexus encodes a novel 1990-amino acid protein with cysteine-rich motifs. Plexus protein was ubiquitously expressed and was tightly associated with the nuclear matrix. In plexus mutant wing imaginal discs, an anteroposterior positional coordinate was established normally as revealed by the wild-type pattern of spalt major and knirps expression. However, the expression of several vein-specific and intervein-specific genes was misregulated, as if they had neglected the positional coordinate. These results suggest that Plexus is an essential component of a global repressor of vein differentiation. Although Plexus protein was expressed in vein primordia of the wing disc, it does not appear to interfere with vein differentiation in the normal position. A genetic epistasis test between px and knirps suggests that plexus acts downstream of knirps. We propose that the vein differentiation takes place by inactivation of the plexus-mediated repression by prepattern genes such as knirps. Plexus may regulate transcription of vein-and intervein-specific genes by tethering transcriptional regulators to specific locations in the nucleus.

Amino Acid Sequence↗