Journal of Cellular Biochemistry Supplement 35:1±2 (2000)

VIEWPOINT

Nuclear Structure and Cancer

Gary Stein, Ronald Berezney, and Robert Getzenberg

There is the emerging recognition that place-ment of regulatory components of gene ex-pression must be temporarily and spatiallycoordinated to facilitate biological control. Theconsequences of breeches in nuclear structure-function relationships are observed in anexpanding series of diseases. Compromisedinterrelationships of nuclear structure withgene expression are illustrated by the modi®edsubnuclear organization of genes and regula-tory factors in cancer. A common feature to allcancers is that they exhibit striking alterationsin nuclear morphology as well as in therepresentation and intranuclear distributionof nucleic acids and regulatory proteins thatare linked to aberrant replication, repair, andtranscriptional control during the onset andprogression of tumorigenesis.

It is becoming increasingly evident thatcontrol of replication and gene expression mustbe understood within the three-dimensionalcontext of nuclear architecture. It is essentialto mechanistically account for compartmentali-zation of replication and transcriptional machi-nery in microenvironments within the nucleuswhere regulatory signals can be integrated andthreshold concentrations for protein/DNA andprotein/protein interactions can be attained.Cancer-related perturbations in the compo-sition, organization, assembly, activity, andintranuclear localization of transcriptional andreplicationcomplexesre¯ectsobligatorycriteriafor stringent control.

This special issue of Journal of CellularBiochemistry is dedicated to exploring concepts,experimental approaches, and novel insightsinto fundamental parameters of nuclear struc-ture and function that relate to the organizationand activities of nucleic acids and regulatoryproteins within the nucleus. It is realistic toanticipate that mechanisms which organizegenes as well as transcription and replicationfactors into functional complexes will providenovel options for cancer diagnosis and targetedtherapies.

Current thinking about the organization ofDNA in nuclear matrix-associated loop domainsand the relevance of subnuclear compartmen-talization for accuracy in transcription, replica-tion, and competency for repair are evaluated[see articles by Bode et al.; Sotolongo and Ward].Unbase paired region-binding proteins areaddressed within the context of loop domain-mediated regulatory activities and modi®ca-tions in tumors [see article by Galande andKohwi-Shigematsu]. The growing appreciationfor the requirement of fundamental interrela-tionships between nuclear and cyto-architec-ture as well as with the extracellular matrix fortransduction of regulatory signals that modu-late chromatin remodeling is presented.Emphasis is on alterations in cancer cells [seearticle by Spencer and Davie]. Recent advancesin tumor-related perturbations in chromatinremodeling [see articles by Bresnick et al.] andrearrangements of chromatin domains in can-cer cells [see articles by Vassetzky et al.; Singhet al.] are evaluated from the perspective ofimpact on the etiology of cancer.

Organization of the regulatory machinery forreplication and transcription at subcellularsites necessitates mechanisms to direct factorsto locations within the nucleus where activityoccurs. Several articles focus on identi®cationand characterization of intranuclear traf®ckingsignals in transcription factors and modi®ca-tions in the intranuclear targeting of regulatoryproteins that are causally related to cancer [seearticles by Jackson; Stein et al.; Leonhardt andCardoso; Meyers and Hiebert; Stenoien et al.].Consistent with observed changes in the intra-nuclear organization of regulatory proteins intumor cells, there is compelling evidence forsegregation of acentric chromosomes duringtumor cell mitosis [see article by Kanda andWahl].

The full complement of regulatory signalsthat mediate control of gene expression in con-junction with components of nuclear archi-tecture remain to be de®ned. However, the

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repertoire of nuclear matrix-associated signal-ing molecules that are targets for cancer-relatedmodi®cations has been extended to includelectins [see articles by Chay and Pienta; Dep-pert et al.] and serine/threonine kinase CK2[see article by Ahmed et al.]. One can beoptimistic that there are viable applications ofnuclear structure/function interrelationshipsto cancer diagnosis and therapy. Nuclearmatrix proteins are providing tumor markers[see article by Davido and Getzenberg]. Cancerrelated disintegration of nuclear organizationhas been causally related to therapeutic out-come of radiation and thermal therapy [seearticle by Roti Roti et al.] and quantitativenuclear morphometry is providing a new gen-eration of parameters for tumor diagnosis,staging, and monitoring of progression [seearticle by Veltri et al.].

Thus, relationships between subnuclear or-ganization and activities of nucleic acids andregulatory proteins is being translated toincreased understanding of fundamental bi-ological control and changes that occur incancer. A challenge we now face is to furtherde®ne tumor-related changes in architecturalorganization of regulatory machinery for repli-cation and transcription within the nucleus.Each step in the assembly and activity ofregulatory complexes at intranuclear sitesrequires a complex and interdependent seriesof events. But, every component of nuclearbiochemistry and morphology contributes tospeci®city for physiological responsiveness aswell as potential targets for tumor diagnosis andtherapies with high speci®city and minimaltoxicity.

2 Stein et al.