The Nuclear Matrix: A Structural Milieu for Genomic Function

Berezney, Ronald; Mortillaro, M; Ma, Hong; Wei, Xiangyun; Samarabandu, Jagath

doi:10.1016/s0074-7696(08)61228-0

Cited by 213 publications

(275 citation statements)

References 194 publications

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“…Investigations of NMPs and how they are linked to the cytoskeleton have already led to a better understanding of nuclear pores, matrix-associated regions of DNA, and how molecular components of the nucleus are integrated into the machinery of replication, transcription, and posttranscriptional events (7,27).…”

Section: Discussionmentioning

confidence: 99%

Engineering gene expression and protein synthesis by modulation of nuclear shape

Thomas

Collier

Sfeir

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

443

326

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The current understanding of the relationships between cell shape, intracellular forces and signaling, nuclear shape and organization, and gene expression is in its infancy. Here we introduce a method for investigating gene-specific responses in individual cells with controlled nuclear shape and projected area. The shape of the nuclei of primary osteogenic cells were controlled on microfabricated substrata with regiospecific chemistry by confining attachment and spreading of isolated cells on adhesive islands. Gene expression and protein synthesis were altered by changing nuclear shape. Collagen I synthesis correlated directly with cell shape and nuclear shape index (NSI), where intermediate values of nuclear distension (6 < NSI < 8) promoted maximum synthesis. Osteocalcin mRNA, a bone-specific differentiation marker, was observed intracellularly by using reverse transcription in situ PCR at 4 days in cells constrained by the pattern and not detected in unconstrained cells of similar projected area, but different NSI. Our data supports the concept of gene expression and protein synthesis based on optimal distortion of the nucleus, possibly altering transcription factor affinity for DNA, transport to the nucleus, or nuclear matrix organization. The combination of microfabricated surfaces, reverse transcription in situ PCR, and NSI measurement is an excellent system to study how transcription factors, the nuclear matrix, and the cytoskeleton interact to control gene expression and may be useful for studying a wide variety of other cell shape͞gene expression relationships.patterning ͉ cell size ͉ osteocalcin ͉ reverse transcription-PCR ͉ photolithography C ell morphology has a profound effect on a range of cellular events, such as proliferation (1-3), differentiation (4-7), cytoskeletal organization (8), and presumably gene expression. Changes to the cytoskeleton lead to altered stress levels imparted on the nucleus (9-11) and could affect organelle and DNA organization and distribution, ultimately altering cell function. For example, the rate of albumin secretion from hepatocytes can be altered by constraining cell size on patterned culture surfaces (3). In human epidermal kareatinocytes cell shape can modulate between terminal differentiation and proliferation (4). Furthermore, cells can be forced to enter the apoptotic cascade when the area on which the cell is allowed to spread is constrained (1). One proposed mechanism for the transduction of cell shape information into gene expression is through mechanical forces transmitted by means of the direct link of the cytoskeleton to the nucleus (9, 12), and in particular to nuclear matrix proteins (NMPs) such as NMP-1 and NMP-2 (13). These architectural transcription factors, which are components of the nuclear scaffold, induce changes in DNA supercoiling and can interact directly with gene promoter sequences (14). This interaction between the nuclear architecture and regulation of transcription or DNA topography raises the question of whether gross deformation of th...

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Section: Discussionmentioning

confidence: 99%

Engineering gene expression and protein synthesis by modulation of nuclear shape

Thomas

Collier

Sfeir

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

443

326

View full text Add to dashboard Cite

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“…In addition to their structural role, nuclear matrix proteins are involved in regulating gene expression, DNA replication and repair (reviewed in [54][55][56][57]). The folding of chromatin facilitates interactions between remote genomic regions to enable or repress transcription, and also enables individual genomic regions to be insulated from the surrounding regions [22,57,58].…”

Section: Generation Of Chromosome Rearrangementsmentioning

confidence: 99%

The role of nuclear organization in cancer

Lever¹,

Sheer²

2009

The Journal of Pathology

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The functional significance of changes in nuclear structure and organization in transformed cells remains one of the most enigmatic questions in cancer biology. In this review, we discuss relationships between nuclear organization and transcription in terms of the threedimensional arrangement of genes in the interphase cancer nucleus and the regulatory functions of nuclear matrix proteins. We also analyse the role of nuclear topology in the generation of gene fusions. We speculate that this type of multi-layered analysis will one day provide a framework for a more comprehensive understanding of the genetic origins of cancer and the identification of new therapeutic targets.

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“…These proteins have been implicated in malignant transformation (Fey and Penman, 1984;Getzenberg et al, 1996), such as alterations in DNA ploidy, DNA content, nuclear shape and proliferative states (Berezney et al, 1995). The nuclear matrix protein termed nuclear restricted protein in brain (NRP/B) (Kim et al, 1998), also known as ENC-1 (Hernandez et al, 1997), was characterized as a Kelch-related protein.…”

Section: Introductionmentioning

confidence: 99%

NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors

et al. 2008

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Brain tumors are associated with genetic alterations of oncogenes and tumor suppressor genes. Accumulation of reactive oxygen species (ROS) in cells leads to oxidative stress-induced damage, resulting in tumorigenesis. Here, we showed that the nuclear matrix protein nuclear restricted protein in brain (NRP/B) was colocalized and interacted with NF-E2-related factor 2 (Nrf2). During oxidative stress response, NRP/B expression and its interaction with Nrf2 were upregulated in SH-SY5Y cells. Association of NRP/B with Nrf2 was crucial for NAD(P)H:quinone oxidoreductase 1 (NQO1) expression. NRP/B was localized predominantly in the nucleus of normal brain cells, whereas in primary brain tumors NRP/B was almost exclusively contained in the cytoplasm. In addition, unlike wild-type NRP/B, the expression of NRP/B mutants isolated from primary brain tumors was found in the cytoplasm, and these mutants failed to induce Nrf2-dependent NQO1 transcription. Thus, NRP/B mutations and their altered localization resulted in changes in NRP/B function and deregulation of Nrf2-dependent NQO1 activation in brain tumors. This study provides insights into the mechanism by which the NRP/B modulates Nrf2-dependent NQO1 induction in cellular protection against ROS in brain tumors.

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The Nuclear Matrix: A Structural Milieu for Genomic Function

Cited by 213 publications

References 194 publications

Engineering gene expression and protein synthesis by modulation of nuclear shape

Engineering gene expression and protein synthesis by modulation of nuclear shape

The role of nuclear organization in cancer

NRP/B mutations impair Nrf2-dependent NQO1 induction in human primary brain tumors

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