Begell House Inc.
Critical Reviews™ in Eukaryotic Gene Expression
CRE
1045-4403
6
2-3
1996
The Utilization of Nuclear Matrix Proteins for Cancer Diagnosis
103-113
10.1615/CritRevEukarGeneExpr.v6.i2-3.10
Tracy S.
Replogle-Schwab
The University of Michigan Comprehensive Cancer Center and Division of Hematology/Oncology, Department of Internal Medicine, 5510 MSRB 1,1150 W. Medical Center Drive, Ann Arbor, Michigan, 48109-0680
Kenneth J.
Pienta
Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Ml 48109-0680
Robert H.
Getzenberg
University of Pittsburgh Cancer Institute, В ST ЕЮ56, 200 Lothrop Street, Pittsburgh, Pennsylvania, 15213-2582
biomarkers
nuclear skeleton
DNA organization
nuclear scaffold.
There is a great need for improved biomarkers in the areas of cancer diagnosis and treatment. Cancer-specific nuclear matrix proteins may provide clinicians with improved biomarkers for earlier diagnosis as well as improved therapies. The nuclear matrix is the RNA-protein skeleton of the nucleus that has structural and functional roles within the cell. Nuclear matrix proteins of a variety of cell lines and tissues, both normal and cancerous, have now been examined and are beginning to be characterized. After comparison of tumor and normal cell nuclear matrix protein compositions, it has been determined that there are a set of proteins common to all tissues as well as distinct tissue-specific and cancer-specific differences. It is these protein differences that provide possible novel biomarkers that may allow for earlier detection of cancer and thus potentially increase the chance of survival.
Scaffold/Matrix-Attached Regions: Topological Switches with Multiple Regulatory Functions
115-138
10.1615/CritRevEukarGeneExpr.v6.i2-3.20
Jurgen
Bode
GBF, National Center for Biotechnologioal Research, D-38124 Braunschweig, Mascheroder Weg 1
Michaela
Stengert-lber
GBF, Gesellschaft fur Biotechnologische Forschung m.b.H., Genetik von Eukaryonten, D-38124 Braunschweig, Mascheroder Weg 1
Volker
Kay
GBF, Gesellschaft fur Biotechnologische Forschung m.b.H., Genetik von Eukaryonten, D-38124 Braunschweig, Mascheroder Weg 1
Thomas
Schlake
DKFZ, Abt. 0425 (Prof. Boehm), Raum 302, Im Neuheimer Feld 280, D-69120 Heidelberg.
Antje
Dietz-Pfeilstetter
BBA, Biologische Bundesanstalt, Institut fur Biochemie und Pflanzenvirologie, D-38104 Braunschweig, Messeweg 11/12
nuclear matrix
topoisomerization
superhelical tension
gene activity
nuclear compartmentalization
protein-DNA interaction.
The nuclear matrix or scaffold that can be prepared and investigated in vitro has an affinity for distinct topological forms of DNA and for sequences that permit the induction of such a topology by their association with a corresponding set of proteins (so-called matrix- or scaffold-attached regions, S/MARs). As a consequence, S/MARs are regarded as topological sinks that can be regulated according to activity-related requirements. Here we develop a switching model to understand the biological functions of S/MARs, which are able to augment transcriptional processes and form barriers between independently regulated domains. The current literature is screened for examples supporting such a mechanism and novel approaches are suggested for their further elucidation.
The Unique, Complex Organization of the Transcriptionally Silent Sperm Chromatin
139-147
10.1615/CritRevEukarGeneExpr.v6.i2-3.30
W. Steven
Ward
Division of Urology, Robert Wood Johnson Medical School, New Brunswick, NJ
Andrei O.
Zalensky
Department of Biological Chemistry, University of California, Davis, CA
sperm chromatin
sperm nucleus
DNA structure
The sperm nucleus contains one haploid copy of the genome that is completely transcriptionally silent and is not being replicated. Recent evidence has revealed that this "silent" chromatin nevertheless contains a complex organization at all levels. This includes DNA loop domain formation by the sperm nuclear matrix that is gene specific and highly ordered folding patterns of the chromosomes, particularly with respect to centromere and telomere positioning. Such specificity in the sperm DNA organization suggests functional requirements for their existence. As these begin to emerge, the sperm nucleus is becoming an important model for the study of the eukaryotic genome.
The Nucleosomal Array: Structure/Function Relationships
149-188
10.1615/CritRevEukarGeneExpr.v6.i2-3.40
Terace M.
Fletcher
The Cancer Therapy and Research Center, Institute for Drug Development, 14960 Omicron Dr., San Antonio, TX 78245-3217
Jeffrey C.
Hansen
Department of Biochemistry, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7760
histones
DNA
chromosome
transcription
replication
macromolecular assembly
A nucleosomal array consists of core histone octamer-DNA complexes spaced at ∼200 bp intervals along a DNA molecule. Nucleosomal arrays are the fundamental building block of chromosomal superstructures, the substrate for transcription, and the first nucleoprotein assembly laid down after DNA replication. The development of homogeneous length-defined nucleosomal arrays has led to a greatly improved understanding of nucleosomal array structural dynamics in the solution state. Under physiological salt conditions, a nucleosomal array is in dynamic equilibrium between folded, self-associated and dissociated conformational states. Folding and self-association are both critically dependent on the core histone tail domains, consistent with an essential functional role for the tail domains in the mediation of chromosomal level DNA compaction in the nucleus. Nucleosomal array folding is repressive to transcription in vitro, but can be overcome by compositional (e.g., tail domain acetylation) and configurational (e.g., histone octamer depletion) changes that are correlated with transcriptional activation in vivo. The mechanism of replication-coupled chromatin assembly also appears to be functionally linked to the dynamic properties of nucleosomal arrays. Although once thought to be both structurally and functionally inert, it is now apparent that the nucleosomal array is a key participant in the biological processes that take place within the chromosomal fibers of eukaryotes.
Utilization of Nuclear Matrix Proteins for Cancer Diagnosis
189-214
10.1615/CritRevEukarGeneExpr.v6.i2-3.50
Susan K.
Keesee
Matritech, Inc., 330 Nevada St., Newton, MA 02160
Joseph V.
Briggman
Matritech, Inc., 330 Nevada St., Newton, MA 02160
Gregory
Thill
Matritech, Inc., 330 Nevada St., Newton, MA 02160
Ying-Jye
Wu
Matritech, Inc., 330 Nevada St., Newton, MA 02160
tumor marker
bladder cancer
prostate cancer
NuMA.
Circulating tumor markers have been used increasingly in recent years as clinical tools for cancer diagnosis and management. This review presents a brief discussion of currently available tumor-associated antigens. Included is an overview of different functional classes of circulating markers and their clinical applications. The limitations of some traditional tumor markers presently in widespread use are discussed in the context of the properties exhibited by an ideal tumor marker. The nuclear matrix provides structural support for the nucleus and plays a dynamic role in the spatial organization of the genome and in the control of DNA replication and transcription. The recovery of increased amounts of specific nuclear matrix proteins in several different cancers has led to the further study of some of these proteins as a new class of tumor markers. Progress on the use of a nuclear matrix protein known as NuMA as a marker for bladder cancer is presented, including results of a recently completed multisite clinical trial. Additional studies on the potential utility of nuclear matrix proteins as markers for prostate cancer are also presented. Nuclear matrix proteins could provide for the development of assays with increased efficacy for the diagnosis and treatment of cancer.
Nuclear Domains Involved in RNA Synthesis, RNA Processing, and Replication
215-246
10.1615/CritRevEukarGeneExpr.v6.i2-3.60
Luitzen
de Jong
E.C. Slater Instituut, University of Amsterdam, Plantage Muidergracht 12, 1018 TV Amsterdam, The Netherlands
Marjolein A.
Grande
E.C. Slater Instituut, University of Amsterdam, Plantage Muidergracht 12, 1018 TV Amsterdam, The Netherlands
Karin A.
Mattern
E.C. Slater Instituut, University of Amsterdam, Plantage Muidergracht 12, 1018 TV Amsterdam, The Netherlands
Wouter
Schul
E.C. Slater Instituut, University of Amsterdam, Plantage Muidergracht 12, 1018 TV Amsterdam, The Netherlands
Roel
van Driel
E.C. Slater Instituut, University of Amsterdam, Plantage Muidergracht 12, 1018 TV Amsterdam, The Netherlands
chromosome territory
clusters of interchromatin granules
nuclear bodies
hnRNP proteins
nuclear matrix
PML.
Two main principles of nuclear organization have been outlined on the basis of contributions by many research groups in recent years. The first principle is that interphase chromosomes occupy discrete territories in the nucleus, with no intermingling of the DNA from different chromosomes. Within a chromosome territory the DNA is organized in chromatin fibers at several levels of folding, that meander through the territory. Transcription and replication take place at the surface of these higher order chromatin fibers, probably on locally unfolded DNA templates. The second principle is that different types of nuclear domains are associated with several specific gene loci. This holds for clusters of interchromatin granules, coiled bodies, RNA 3’ cleavage factor-containing nuclear bodies (cleavage bodies) and probably PML-containing nuclear bodies. These domains may play an important role in the spatial arrangement of genes in the interphase nucleus. Despite these new insights, our knowledge of the function of many nuclear compartments and the molecular interactions responsible for the dynamic organization of a compartmentalized nucleus is still in its infancy.
Functional Architecture of Chromosomal DNA Domains
247-269
10.1615/CritRevEukarGeneExpr.v6.i2-3.70
Sergey V.
Razin
Laboratory of Structural and Functional Organization of hromosomes, Institute of Gene Biology of the Russian Academy of Sciences, Vavilov Str. 34/5, 117334 Moscow, Russia
chromosomal DNA loops
nuclear matrix DNA
topoisomerase II-mediated DNA loop excision
apoptosis
position dependence of transgene expression.
More than 20 years ago, it was found that chromosomal DNA in eukaryotic cell nuclei was organized into large loops by periodic attachment to the high salt-insoluble proteinous nuclear (chromosomal) matrix. The specificity of genomic DNA partitioning into loops has been studied intensively trying to find out whether loops may constitute quasiindependent structural-functional units of the genome. These studies have resulted in conflicting findings and, consequently, in conflicting conclusions.
Recently, we have developed a conceptually new approach for analysis of specificity of the DNA loop organization by topoisomerase II-mediated excision of individual loops and their oligomers. Using this approach we have obtained new data supporting the supposition that loops may constitute the basic units of genome organization and evolution.
In the present article we critically analyze all existing data on specificity and functional significance of chromosomal DNA organization into loops. The goals of this analysis is:
1. To evaluate the available experimental data and try to understand the reasons of the conflicting results obtained by different experimental approaches.
2. Try to answer the long-standing question about a possible correlation between the functional organization of the genome and the mode of its packaging within the nuclei.
Interrelationships between Nuclear Structure and Ligand-Activated Intracellular Receptors
271-283
10.1615/CritRevEukarGeneExpr.v6.i2-3.80
Mary F.
Ruh
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104
Robert
Dunn, II
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104
Thomas S.
Ruh
Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, MO 63104
estrogen receptor
steroid hormone receptors
Ah receptor
dioxin
nuclear matrix
histones
nucleosomes.
The role of ligand-activated intracellular receptors in activation of gene expression most probably involves a multistep process that requires alteration in chromatin structure. Results of studies with members of the steroid hormone receptor superfamily as well as the ligand-activated member of the basic region/helix-loop-helix family of transcriptional activators suggests that two different nuclear structures and their associated nuclear proteins are important in the initial stages of gene activation: the nuclear matrix and nucleosomes. Cell- and tissue-specific nuclear matrix proteins and the variant and modified histones appear to be important for tissue and species specificity of ligand-induced responses. Because the function of a receptor may be limited in vivo by promoter and transcription factor accessibility, the various roles of nuclear ligand-receptor complexes may involve interaction with nuclear matrix proteins and/or nucleosomes. Tissue-specific structural nuclear proteins could control the conformation (looping through matrix attachment regions) of the DNA and unwinding or rearrangement of nucleosomes, thus providing specificity to the expression of certain genes. Modulation of cooperative elements required for gene activation may involve association of the gene promoter with the nuclear matrix together with the presence of nucleosomes. Thus, the series of events involved in ligand-receptor activation of genes requires alterations in chromatin structure, which allow access of the receptor complex to elements within the gene.
Regulation of the Chicken Lysozyme Locus in Transgenic Mice
285-297
10.1615/CritRevEukarGeneExpr.v6.i2-3.90
Constanze
Bonifer
Institut fur Biologie III, Universitat Freiburg, Schanzlestr.1, D-79104 Freiburg i. Br., Germany
Matthias C.
Huber
Institut fur Biologie III, Universitat Freiburg, Schanzlestr.1, D-79104 Freiburg i. Br., Germany
Nicole
Faust
Institut fur Biologie III, Universitat Freiburg, Schanzlestr.1, D-79104 Freiburg i. Br., Germany
Albrecht E.
Sippel
Institut fur Biologie III, Universitat Freiburg, Schanzlestr.1, D-79104 Freiburg i. Br., Germany
Chicken lysozyme gene
transgenic mice
phased nucleosomes
genomic position effects
evolu¬tion of gene regulation.
The chicken lysozyme locus is transcriptionally activated during macrophage differentiation. Each cis-regulatory element has its unique activation stage during cell differentiation, whereby maximal transcriptional activity of the gene is only observed when all cis-elements are active. The complete chicken lysozyme locus is expressed position independently and at a high level in macrophages of transgenic mice. For correct transgene regulation, the cooperation of all cis-regulatory elements is required. These cis-regulatory elements specify the mode of regulation and we observe the same expression pattern of the transgene in the mouse and the endogenous gene in chicken macrophages. This indicates that the transcription factors responsible for chicken lysozyme regulation are highly conserved in evolution. The endogenous mouse lysozyme gene is regulated differently. The chromatin of the lysozyme locus is highly structured in the transcriptionally active, as well as in the inactive state. The transcriptional activation of the lysozyme locus is accompanied by extensive chromatin rearrangements, which are disturbed when one essential cis-regulatory element is deleted and the transgenes are subjects to genomic position effects. Based on these results, we propose that a distinct chromatin architecture of a gene locus is required for its correct activation.