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  • Review Article
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Nuclear microenvironments in biological control and cancer

Nature Reviews Cancer volume 7, pages 454–463 (2007)Cite this article

Key Points

  • The biological control of gene expression requires the temporal and spatial integration of dynamic processes. These include nuclear import, intranuclear targeting and chromatin remodelling that facilitate the organization and assembly of gene-regulatory machinery in microenvironments within the cell nucleus.

  • Combinatorial assembly and organization of nuclear microenvironments is mediated by scaffolding proteins at several sites in target gene promoters as well as in subnuclear domains. Such focal compartmentalization of regulatory machinery in nuclear microenvironments might regulate the dynamic formation and activity of physiologically responsive regulatory networks and provide threshold concentrations of factors that govern the extent to which genes are activated, suppressed or coordinately controlled.

  • Targeting of scaffolding proteins to specific sites within the nucleus supports their involvement in biological control and reflects the potential influence of cancer-related alterations on gene expression.

  • Solid tumours, leukaemias and lymphomas show striking alterations in nuclear morphology as well as in the architectural organization of genes, transcripts and regulatory complexes within the nucleus. Examples of altered nuclear microenvironments include promyelocytic leukaemia (PML) bodies and acute myeloid leukaemia (AML) foci in leukaemias, the nucleolus in some solid tumours and extensive chromosomal rearrangements.

  • Imaging principal nuclear compartments that are frequently rearranged in cancer combined with genomic and proteomic analyses can improve the biological and clinical relevance of regulatory signatures produced as a result of high throughput gene profiling of tumours.

  • Mechanistic insights into the temporal and spatial organization of the nuclear machinery involved in gene expression, which is compromised in tumours, provide a novel platform for diagnosis and therapy.

Abstract

Nucleic acids and regulatory proteins are compartmentalized in microenvironments within the nucleus. This subnuclear organization may support convergence and the integration of physiological signals for the combinatorial control of gene expression, DNA replication and repair. Nuclear organization is modified in many cancers. There are cancer-related changes in the composition, organization and assembly of regulatory complexes at intranuclear sites. Mechanistic insights into the temporal and spatial organization of machinery for gene expression within the nucleus, which is compromised in tumours, provide a novel platform for diagnosis and therapy.

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Figure 1: Perturbations in nuclear microenvironments in cancer.
Figure 2: Several trafficking signals localize regulatory proteins to the right place at the right time.

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Acknowledgements

Studies reported in this article were in part supported by grants from the US National Institutes of Health. The authors thank B. Bronstein for editorial assistance with the preparation of the manuscript.

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  1. Daniel W. Young & Martin Montecino

    Present address: Present address: Novartis Institute for Biomedical Research, Platform and Chemical Biology – Proteome Sciences, Cambridge, Massachusetts, USA.,

Authors and Affiliations

  1. University of Massachusetts Medical School and UMASS Memorial Cancer Center, Worcester, Massachusetts, USA

    Sayyed K. Zaidi, Daniel W. Young, Amjad Javed, Jitesh Pratap, Andre van Wijnen, Jane B. Lian & Janet L. Stein

  2. University of Alabama at Birmingham School of Dentistry, Institute of Oral Health Research, Birmingham, Alabama, USA

    Gary S. Stein

  3. Departamento de Bioquimica y Biologia Molecular, Universidad de Concepcion, Facultad de Ciencias Biologicas, Concepcion, Chile

    Amjad Javed

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Glossary

Nuclear microenvironments

Dynamic, microscopically visible, regulatory sites (domains) within the nucleus that are organized and assembled by scaffolding proteins.

Scaffolding proteins

Nuclear scaffolding proteins are regulatory factors that bind to DNA in a sequence-specific manner, associate with the nuclear matrix and interact with co-activators and co-suppressors to regulate transcription, replication and repair.

Runx

A family of three mammalian Runx transcription factors control three distinct lineage commitments (RUNX1 in haematopoiesis; RUNX2 in osteogenesis; and RUNX3 in neurogenesis and gut development) and regulate cell growth, differentiation and proliferation.

Acrocentric chromosomes

An acrocentric chromosome is one in which the centromere is located very near to one of the ends of the chromosome, thus making the short arm of the chromosome negligible. Human chromosomes 13, 14, 15, 21 and 22 are acrocentric chromosomes and all have genes that encode rRNAs.

TH2 response

A T-helper-2 response involves the production of cytokines, such as IL4, which stimulate antibody production. TH2 cytokines promote secretory immune responses of mucosal surfaces to extracellular pathogens and allergic reactions.

Intranuclear targeting

Directed movement of regulatory proteins within the nucleus to specific nuclear microenvironments.

Nuclear matrix targeting signal

(NMTS) The NMTS is a 30–40 amino acid sequence that directs regulatory proteins to nuclear matrix-associated sites and is unique in structure and sequence.

Nuclear matrix

An architectural network of ribonuclear proteins within the nucleus that is retained following the removal of soluble cytoplasmic and nuclear proteins as well as chromatin.

Intranuclear informatics

A mathematical alogrithm that uses 28 independent parameters to quantitatively assess subnuclear organization of regulatory proteins.

Architectural signature

A quantitative representation of subnuclear organization that is specific for each protein.

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Zaidi, S., Young, D., Javed, A. et al. Nuclear microenvironments in biological control and cancer. Nat Rev Cancer 7, 454–463 (2007). https://doi.org/10.1038/nrc2149

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