Organization of transcriptional regulatory machinery in nuclear microenvironments: Implications for biological control and cancer

Stein, Gary S.; Lian, Jane B.; Wijnen, André J. van; Stein, Janet L.; Javed, Amjad; Montecino, Martín; Choi, Je‐Yong; Vradii, Diana; Zaidi, Sayyed K.; Pratap, Jitesh; Young, Daniel W.

doi:10.1016/j.advenzreg.2006.12.014

Cited by 21 publications

(18 citation statements)

References 51 publications

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“…The nuclear lamin scaffold in turn, may influence nuclear organization, chromatin modification, transcriptional regulation and mRNA processing. Specific nuclear scaffold proteins such as RUNX have also been implicated in regulation of differentiation (Stein et al, 2007). RUNX is a negative regulator of the segment polarity gene, engrailed in Drosophila and the thymocyte specification factor CD4 in mice (Durst and Hiebert, 2004).…”

Section: Ecm In Differentiationmentioning

confidence: 99%

The extracellular matrix in development and morphogenesis: A dynamic view

Rozario

DeSimone

2010

Developmental Biology

1,199

927

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The extracellular matrix (ECM) is synthesized and secreted by embryonic cells beginning at the earliest stages of development. Our understanding of ECM composition, structure and function has grown considerably in the last several decades and this knowledge has revealed that the extracellular microenvironment is critically important for cell growth, survival, differentiation and morphogenesis. ECM and the cellular receptors that interact with it mediate both physical linkages with the cytoskeleton and the bidirectional flow of information between the extracellular and intracellular compartments. This review considers the range of cell and tissue functions attributed to ECM molecules and summarizes recent findings specific to key developmental processes. The importance of ECM as a dynamic repository for growth factors is highlighted along with more recent studies implicating the 3-dimensional organization and physical properties of the ECM as it relates to cell signaling and the regulation of morphogenetic cell behaviors. Embryonic cell and tissue generated forces and mechanical signals arising from ECM adhesion represent emerging areas of interest in this field.

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Section: Ecm In Differentiationmentioning

confidence: 99%

The extracellular matrix in development and morphogenesis: A dynamic view

Rozario

DeSimone

2010

Developmental Biology

1,199

927

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“…The differences in the number of receptor sites and the complexity of the CSK -NSK network that mechanically connect the extracellular matrix to the nucleus, between the young and the aged cells, could result in a difference in stimulation patterning in the nucleus, as shown in Figure 6. Nuclear strain has been suggested to influence higher-order chromatin organisation, thereby restricting or promoting the accessibility of transcription factors or other regulatory factors to specific gene sequences, which could similarly influence gene transcription (Stein et al 2007). …”

Section: Discussionmentioning

confidence: 99%

Effect of membrane stiffness and cytoskeletal element density on mechanical stimuli within cells: an analysis of the consequences of ageing in cells

Xue

Lennon

McKayed

et al. 2013

Computer Methods in Biomechanics and Biomedical Engineering

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“…Aside from binding to the chromatin, RUNX proteins also associate with microtubules (9,10). RUNX3 molecules are detected at key mitotic structures such as the centrosome, mitotic spindle, and midbody (11).…”

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confidence: 99%

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Chuang

Khor

Lai

et al. 2016

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

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The Runt-related transcription factors (RUNX) are master regulators of development and major players in tumorigenesis. Interestingly, unlike most transcription factors, RUNX proteins are detected on the mitotic chromatin and apparatus, suggesting that they are functionally active in mitosis. Here, we identify key sites of RUNX phosphorylation in mitosis. We show that the phosphorylation of threonine 173 (T173) residue within the Runt domain of RUNX3 disrupts RUNX DNA binding activity during mitotic entry to facilitate the recruitment of RUNX proteins to mitotic structures. Moreover, knockdown of RUNX3 delays mitotic entry. RUNX3 phosphorylation is therefore a regulatory mechanism for mitotic entry. Cancer-associated mutations of RUNX3 T173 and its equivalent in RUNX1 further corroborate the role of RUNX phosphorylation in regulating proper mitotic progression and genomic integrity.C ell division is a highly ordered process comprising multiple steps that lead to dramatic changes to the cell architecture. Events such as cell rounding, chromatin condensation, spindle assembly, nuclear envelope disassembly, and cytokinesis involve numerous proteins, whose activities are tightly coordinated by mitotic kinases and proteasome-mediated degradation (1). Given that most transcription has stopped (2), the roles of transcription factors during mitosis are ill explored.Runt-related transcription factors (RUNX) are master regulators of cell-fate decisions (3). Mutation or dysregulation of RUNX genes have been associated with diverse cancer types (3). Unlike many transcription factors (e.g., Ets-1 and Oct-1) (4), RUNX proteins are retained at the condensed mitotic chromatin, where they maintain epigenetic memory and ensure proper transmission of gene expression patterns to progeny cells; RUNX2 binds to the promoters of various cell cycle-and cell fate-related genes and regulates histone modifications during mitosis (5); RUNX2 and RUNX3 bind to regulatory regions of rRNA genes and are associated with their repression (6, 7). RUNX1 positively regulates the transcription of various spindle assembly checkpoint genes, such as BUB1 and NEK6 (8). These findings suggest that RUNX proteins are important for the accurate transmission of genetic information during mitosis and that defects in RUNX genes might contribute to aneuploidy and loss of cell identity.Aside from binding to the chromatin, RUNX proteins also associate with microtubules (9, 10). RUNX3 molecules are detected at key mitotic structures such as the centrosome, mitotic spindle, and midbody (11). Likewise, RUNX-binding partner CBFβ was found at the midbody and implicated in cytokinesis (12). The reason why RUNX proteins are present at non-DNA sites (i.e., mitotic apparatus) during mitosis is unknown. An intriguing observation is the hyperphosphorylation of RUNX proteins during mitosis (13,14). RUNX2 is phosphorylated by mitotic kinase CDK1-cyclin B1 (14, 15) and dephosphorylated at mitotic exit by the PP1/PP2A phosphatase (14). CDK1-mediated phosphorylation of RUNX2 enhanc...

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Organization of transcriptional regulatory machinery in nuclear microenvironments: Implications for biological control and cancer

Cited by 21 publications

References 51 publications

The extracellular matrix in development and morphogenesis: A dynamic view

The extracellular matrix in development and morphogenesis: A dynamic view

Effect of membrane stiffness and cytoskeletal element density on mechanical stimuli within cells: an analysis of the consequences of ageing in cells

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

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