scholarly journals A combinatorial mechanism for determining the specificity of E2F activation and repression

Oncogene ◽  
2009 ◽  
Vol 28 (32) ◽  
pp. 2873-2881 ◽  
Author(s):  
J A Freedman ◽  
J T Chang ◽  
L Jakoi ◽  
J R Nevins
Keyword(s):  
Combinatorial Mechanism

scholarly journals Poison-Exon Inclusion in DHX9 Reduces Its Expression and Sensitizes Ewing Sarcoma Cells to Chemotherapeutic Treatment

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 328 ◽  
Author(s):  
Ramona Palombo ◽  
Veronica Verdile ◽  
Maria Paola Paronetto
Keyword(s):  
Alternative Splicing ◽  
Ewing Sarcoma ◽  
Splicing Factors ◽  
Mrna Variants ◽  
Aggressive Tumor ◽  
Chemotherapeutic Treatment ◽  
Sarcoma Cells ◽  
Combinatorial Mechanism ◽  
Worse Prognosis

Alternative splicing is a combinatorial mechanism by which exons are joined to produce multiple mRNA variants, thus expanding the coding potential and plasticity of eukaryotic genomes. Defects in alternative splicing regulation are associated with several human diseases, including cancer. Ewing sarcoma is an aggressive tumor of bone and soft tissue, mainly affecting adolescents and young adults. DHX9 is a key player in Ewing sarcoma malignancy, and its expression correlates with worse prognosis in patients. In this study, by screening a library of siRNAs, we have identified splicing factors that regulate the alternative inclusion of a poison exon in DHX9 mRNA, leading to its downregulation. In particular, we found that hnRNPM and SRSF3 bind in vivo to this poison exon and suppress its inclusion. Notably, DHX9 expression correlates with that of SRSF3 and hnRNPM in Ewing sarcoma patients. Furthermore, downregulation of SRSF3 or hnRNPM inhibited DHX9 expression and Ewing sarcoma cell proliferation, while sensitizing cells to chemotherapeutic treatment. Hence, our study suggests that inhibition of hnRNPM and SRSF3 expression or activity could be exploited as a therapeutic tool to enhance the efficacy of chemotherapy in Ewing sarcoma.

scholarly journals Optimal combinatorial mechanism design

2012 ◽  
Vol 53 (2) ◽  
pp. 473-498 ◽  
Author(s):  
Levent Ülkü
Keyword(s):  
Mechanism Design ◽  
Combinatorial Mechanism

Causing something to be one way rather than another

Kybernetes ◽  
2014 ◽  
Vol 43 (6) ◽  
pp. 865-881 ◽  
Author(s):  
Barbara Osimani
Keyword(s):  
Genetic Information ◽  
Design Methodology ◽  
Special Kind ◽  
Developmental Systems ◽  
Content Type ◽  
The Common ◽  
Definition Of ◽  
Combinatorial Mechanism ◽  
And Linguistics ◽  
Causal Specificity

Purpose – The purpose of this paper is to suggest a definition of genetic information by taking into account the debate surrounding it. Particularly, the objections raised by Developmental Systems Theory (Griffiths, 2001; Oyama 1985; Griffiths and Knight 1998) to Teleosemantic endorsements of the notion of genetic information (Sterelny et al. 1996; Maynard Smith, 2000; Jablonka, 2002) as well as deflationist approaches which suggest to ascribe the notion of genetic information a heuristic value at most, and to reduce it to that of causality (Godfrey-Smith, 2000; Boniolo, 2003, 2008). Design/methodology/approach – The paper presents the notion of genetic information through its historical evolution and analyses it with the conceptual tools offered by philosophical theories of causation on one side (“causation as influence,” Woodward, 2010; Waters, 2007; Lewis, 2000) and linguistics on the other (“double articulation” Martinet, 1960). Findings – The concept of genetic information is defined as a special kind of cause which causes something to be one way rather than another, by combining elementary units one way rather than another. Tested against the notion of “genetic error” this definition demonstrates to provide an exhaustive account of the common denominators associated with the notion of genetic information: causal specificity; combinatorial mechanism; arbitrariness. Originality/value – The definition clarifies how the notion of information is understood when applied to genetic phenomena and also contributes to the debate on the notion of information, broadly meant, which is still affected by lack of consensus (Floridi, 2013).

scholarly journals Interactions between Germ Cells and Extracellular Matrix Glycoproteins during Migration and Gonad Assembly in the Mouse Embryo

1997 ◽  
Vol 138 (2) ◽  
pp. 471-480 ◽  
Author(s):  
Martín I. García-Castro ◽  
Robert Anderson ◽  
Janet Heasman ◽  
Christopher Wylie
Keyword(s):  
Extracellular Matrix ◽  
Germ Cells ◽  
Binding Sites ◽  
Primordial Germ Cells ◽  
A Cell ◽  
Hind Gut ◽  
Combinatorial Mechanism ◽  
Cell Surface Proteoglycan ◽  
Strength Of Adhesion

Cells are known to bind to individual extracellular matrix glycoproteins in a complex and poorly understood way. Overall strength of adhesion is thought to be mediated by a combinatorial mechanism, involving adhesion of a cell to a variety of binding sites on the target glycoproteins. During migration in embryos, cells must alter their overall adhesiveness to the substrate to allow locomotion. The mechanism by which this is accomplished is not well understood. During early development, the cells destined to form the gametes, the primordial germ cells (PGCs), migrate from the developing hind gut to the site where the gonad will form. We have used whole-mount immunocytochemistry to study the changing distribution of three extracellular matrix glycoproteins, collagen IV, fibronectin, and laminin, during PGC migration and correlated this with quantitative assays of adhesiveness of PGCs to each of these. We show that PGCs change their strength of adhesion to each glycoprotein differentially during these stages. Furthermore, we show that PGCs interact with a discrete tract of laminin at the end of migration. Closer analysis of the adhesion of PGCs to laminin revealed that PGCs adhere particularly strongly to the E3 domain of laminin, and blocking experiments in vitro suggest that they adhere to this domain using a cell surface proteoglycan.

scholarly journals Discrete and Continuous Cell Identities of the Adult Murine Striatum

2019 ◽  
Author(s):  
Geoffrey Stanley ◽  
Ozgun Gokce ◽  
Robert C. Malenka ◽  
Thomas C. Südhof ◽  
Stephen R. Quake
Keyword(s):  
Dopamine Receptor ◽  
D2 Receptor ◽  
Spatial Relationship ◽  
Cell Types ◽  
Projection Neurons ◽  
Anatomical Location ◽  
D2 Dopamine Receptors ◽  
Spatial Gradients ◽  
Dopamine Receptor 1 ◽  
Combinatorial Mechanism

AbstractThe striatum is a large brain region containing two major cell types: D1 (dopamine receptor 1) and D2 (dopamine receptor 2) expressing spiny projection neurons (SPNs). We generated a cell type atlas of the adult murine striatum using single-cell RNA-seq of SPNs combined with quantitative RNAin situhybridization (ISH). We developed a novel computational pipeline that distinguishes discrete versus continuous cell identities in scRNA-seq data, and used it to show that SPNs in the striatum can be classified into four discrete types that reside in discrete anatomical clusters or are spatially intermingled. Within each discrete type, we find multiple independent axes of continuous cell identity that map to spatial gradients and whose genes are conserved between discrete types. These gradients correlate well to previously-mapped gradients of connectivity. Using these insights, we discovered multiple novel spatially localized region of the striatum, one of which contains patch-D2 SPNs that expressTac1, Htr7, andTh. Intriguingly, we found one subtype that strongly co-expresses both D1 and D2 dopamine receptors, and uniquely expresses a rare D2 receptor splice variant. These results collectively suggest an organizational principal of neuron identity in which major neuron types can be separated into discrete classes with little overlap and no implied spatial relationship. However these discrete classes are then continuously subdivided by multiple spatial gradients of expression defining anatomical location via a combinatorial mechanism. Finally, they suggest that neuronal circuitry has a substructure at far higher resolution than is typically interrogated which is defined by the precise identity and location of a neuron.

Positional information revisited

Development ◽  
1989 ◽  
Vol 107 (Supplement) ◽  
pp. 3-12 ◽  
Author(s):  
Lewis Wolpert
Keyword(s):  
Cell Differentiation ◽  
Molecular Basis ◽  
Positional Information ◽  
Good Evidence ◽  
Polar Coordinate ◽  
History Of ◽  
Development And Differentiation ◽  
A Cell ◽  
Combinatorial Mechanism ◽  
Positional Value

Positional information has been suggested to play a central role in pattern formation during development. The strong version of positional information states that there is a cell parameter, positional value, which is related to position as in a coordinate system and which determines cell differentiation. A weaker version merely emphasises position as a key determinant in cell development and differentiation. There is evidence for boundaries and orthogonal axes playing an important role in positional systems. A positional signal is distinguished from an inductive interaction because the former specifies multiple states, confers polarity, and can act over a long range. A gradient in a diffusible morphogen is just one way of specifying position. There is now good evidence in several systems for substances which may be the morphogen for positional signalling. The product of the bicoid gene in early Drosophila development is the best prospect. Retinoic acid is unique in its ability to alter positional value and may also be a morphogen. The best evidence for positional value, a concept fundamental to positional information, remains a biological assay based on grafting. The idea of positional value uncouples differentiation and position, and allows considerable freedom for patterning. It is not clear whether positional value or differentiation involves a combinatorial mechanism. Interpretation of positional information remains a central problem. There is good evidence that cells can respond differentially to less than a two-fold change in concentration of a chemical signal. It may be that interpretation involves listing the sites at which a particular class of cell differentiation will occur. The problem is made less severe when blocks of cells are specified together as in mechanisms based on an isomorphic prepattern. Isomorphic prepatterns could establish repeated structures which are equivalent and which are then made non-equivalent by positional information. This would enable local differences to develop. The combination of these two mechanisms may be widespread. There is evidence that positional signals within a single animal and in related animals are conserved. It is not clear just how wide this conservation is, but it is at phylotypic stages, rather than in eggs, that similarity might be expected. It is nevertheless impressive that the polar coordinate model can be applied to regulation in systems as diverse as insects, vertebrates and protozoa. The molecular basis of positional signalling is just becoming accessible; the molecular basis of positional value is still awaited. A brief personal history of positional information is provided in an appendix.

scholarly journals Low oxygen levels induce the expression of the embryonic morphogen Nodal

2011 ◽  
Vol 22 (24) ◽  
pp. 4809-4821 ◽  
Author(s):  
Daniela F. Quail ◽  
Meghan J. Taylor ◽  
Logan A. Walsh ◽  
Dylan Dieters-Castator ◽  
Padmalaya Das ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Breast Cancer Cells ◽  
Gene Locus ◽  
Low Oxygen ◽  
Cellular Invasion ◽  
Treatment And Prevention ◽  
Combinatorial Mechanism ◽  
Insight Into

Low oxygen (O2) levels characterize the microenvironment of both stem cells and rapidly growing tumors. Moreover, hypoxia is associated with the maintenance of stem cell–like phenotypes and increased invasion, angiogenesis and metastasis in cancer patients. Metastatic cancers, such as breast cancer and melanoma, aberrantly express the embryonic morphogen Nodal, and the presence of this protein is correlated with metastatic disease. In this paper, we demonstrate that hypoxia induces Nodal expression in melanoma and breast cancer cells concomitant with increased cellular invasion and angiogenic phenotypes. Of note, Nodal expression remains up-regulated up to 48 h following reoxygenation. The oxygen-mediated regulation of Nodal expression occurs via a combinatorial mechanism. Within the first 24 h of exposure to low O2, there is an increase in protein stability. This increase in stability is accompanied by an induction of transcription, mediated by the HIF-1α–dependent activation of Notch-responsive elements in the node-specific enhancer of the Nodal gene locus. Finally, Nodal expression is maintained upon reoxygenation by a canonical SMAD-dependent feed-forward mechanism. This work provides insight into the O2-mediated regulation of Nodal, a key stem cell–associated factor, and reveals that Nodal may be a target for the treatment and prevention of hypoxia-induced tumor progression.

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