scholarly journals Rely on Each Other: DNA Binding Cooperativity Shapes p53 Functions in Tumor Suppression and Cancer Therapy

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2422
Author(s):  
Oleg Timofeev ◽  
Thorsten Stiewe
Keyword(s):  
Cancer Therapy ◽  
Dna Binding ◽  
Cell Fate ◽  
Tumor Suppression ◽  
Quaternary Structure ◽  
Three Dimensional ◽  
Structural Basis ◽  
Sequence Specificity ◽  
Cell Fate Decisions ◽  
Cancer Mutations

p53 is a tumor suppressor that is mutated in half of all cancers. The high clinical relevance has made p53 a model transcription factor for delineating general mechanisms of transcriptional regulation. p53 forms tetramers that bind DNA in a highly cooperative manner. The DNA binding cooperativity of p53 has been studied by structural and molecular biologists as well as clinical oncologists. These experiments have revealed the structural basis for cooperative DNA binding and its impact on sequence specificity and target gene spectrum. Cooperativity was found to be critical for the control of p53-mediated cell fate decisions and tumor suppression. Importantly, an estimated number of 34,000 cancer patients per year world-wide have mutations of the amino acids mediating cooperativity, and knock-in mouse models have confirmed such mutations to be tumorigenic. While p53 cancer mutations are classically subdivided into “contact” and “structural” mutations, “cooperativity” mutations form a mechanistically distinct third class that affect the quaternary structure but leave DNA contacting residues and the three-dimensional folding of the DNA-binding domain intact. In this review we discuss the concept of DNA binding cooperativity and highlight the unique nature of cooperativity mutations and their clinical implications for cancer therapy.

Electron Microscopy and image reconstruction reveal the structural basis for spectrin's elastic properties

1992 ◽  
Vol 50 (1) ◽  
pp. 510-511
Author(s):  
Amy M. McGough ◽  
Robert Josephs
Keyword(s):  
Electron Microscopy ◽  
Elastic Properties ◽  
Conformational Changes ◽  
Quaternary Structure ◽  
Three Dimensional ◽  
Membrane Skeleton ◽  
Projection Algorithm ◽  
Structural Basis ◽  
Iterative Approximation ◽  
Membrane Skeletons

The remarkable deformability of the erythrocyte derives in large part from the elastic properties of spectrin, the major component of the membrane skeleton. It is generally accepted that spectrin's elasticity arises from marked conformational changes which include variations in its overall length (1). In this work the structure of spectrin in partially expanded membrane skeletons was studied by electron microscopy to determine the molecular basis for spectrin's elastic properties. Spectrin molecules were analysed with respect to three features: length, conformation, and quaternary structure. The results of these studies lead to a model of how spectrin mediates the elastic deformation of the erythrocyte.Membrane skeletons were isolated from erythrocyte membrane ghosts, negatively stained, and examined by transmission electron microscopy (2). Particle lengths and end-to-end distances were measured from enlarged prints using the computer program MACMEASURE. Spectrin conformation (straightness) was assessed by calculating the particles’ correlation length by iterative approximation (3). Digitised spectrin images were correlation averaged or Fourier filtered to improve their signal-to-noise ratios. Three-dimensional reconstructions were performed using a suite of programs which were based on the filtered back-projection algorithm and executed on a cluster of Microvax 3200 workstations (4).

scholarly journals Control of cellular responses to mechanical cues through YAP/TAZ regulation

2019 ◽  
Vol 294 (46) ◽  
pp. 17693-17706 ◽  
Author(s):  
Ishani Dasgupta ◽  
Dannel McCollum
Keyword(s):  
Cell Fate ◽  
Wound Repair ◽  
Hippo Pathway ◽  
Three Dimensional ◽  
Focal Adhesions ◽  
Mechanical Stimuli ◽  
Cell Contractility ◽  
Cell Fate Decisions ◽  
Disease States ◽  
The Hippo Pathway

To perceive their three-dimensional environment, cells and tissues must be able to sense and interpret various physical forces like shear, tensile, and compression stress. These forces can be generated both internally and externally in response to physical properties, like substrate stiffness, cell contractility, and forces generated by adjacent cells. Mechanical cues have important roles in cell fate decisions regarding proliferation, survival, and differentiation as well as the processes of tissue regeneration and wound repair. Aberrant remodeling of the extracellular space and/or defects in properly responding to mechanical cues likely contributes to various disease states, such as fibrosis, muscle diseases, and cancer. Mechanotransduction involves the sensing and translation of mechanical forces into biochemical signals, like activation of specific genes and signaling cascades that enable cells to adapt to their physical environment. The signaling pathways involved in mechanical signaling are highly complex, but numerous studies have highlighted a central role for the Hippo pathway and other signaling networks in regulating the YAP and TAZ (YAP/TAZ) proteins to mediate the effects of mechanical stimuli on cellular behavior. How mechanical cues control YAP/TAZ has been poorly understood. However, rapid progress in the last few years is beginning to reveal a surprisingly diverse set of pathways for controlling YAP/TAZ. In this review, we will focus on how mechanical perturbations are sensed through changes in the actin cytoskeleton and mechanosensors at focal adhesions, adherens junctions, and the nuclear envelope to regulate YAP/TAZ.

scholarly journals Hyaluronan-Based Three-Dimensional Microenvironment Potently Induces Cardiovascular Progenitor Cell Populations

2013 ◽  
Vol 2013 ◽  
pp. 1-7
Author(s):  
Jessica M. Gluck ◽  
Jennifer Chyu ◽  
Connor Delman ◽  
Sepideh Heydarkhan-Hagvall ◽  
W. Robb MacLellan ◽  
...  
Keyword(s):  
Cell Fate ◽  
Progenitor Cell ◽  
Three Dimensional ◽  
Extrinsic Factors ◽  
Cell Fate Decisions ◽  
3D Microenvironment ◽  
Cell Niche ◽  
The Relationship ◽  
Stem Cell Niches

The relationship between stem cell niches in vivo and their surrounding microenvironment is still relatively unknown. Recent advances have indicated that extrinsic factors within the cardiovascular progenitor cell niche influence maintenance of a multipotent state as well as drive cell-fate decisions. We have previously shown the direct effects of extracellular matrix (ECM) proteins and have now investigated the effects of dimension on the induction of a cardiovascular progenitor cell (CPC) population. We have shown here that the three-dimensionality of a hyaluronan-based hydrogel greatly induces a CPC population, as marked by Flk-1. We have compared the effects of a 3D microenvironment to those of conventional 2D cell culture practices and have found that the 3D microenvironment potently induces a progenitor cell state.

scholarly journals Cell fate transitions and the replication timing decision point

2010 ◽  
Vol 191 (5) ◽  
pp. 899-903 ◽  
Author(s):  
David M. Gilbert
Keyword(s):  
Cell Fate ◽  
Large Scale ◽  
Three Dimensional ◽  
Replication Timing ◽  
Window Of Opportunity ◽  
Decision Point ◽  
Stem Cell Fate ◽  
Cell Fate Decisions ◽  
Timing Decision ◽  
3D Architecture

Recent findings suggest that large-scale remodeling of three dimensional (3D) chromatin architecture occurs during a brief period in early G1 phase termed the replication timing decision point (TDP). In this speculative article, I suggest that the TDP may represent an as yet unappreciated window of opportunity for extracellular cues to influence 3D architecture during stem cell fate decisions. I also describe several testable predictions of this hypothesis.

Clox, a mammalian homeobox gene related to Drosophila cut, encodes DNA-binding regulatory proteins differentially expressed during development

Development ◽  
1992 ◽  
Vol 116 (2) ◽  
pp. 321-334 ◽  
Author(s):  
V. Andres ◽  
B. Nadal-Ginard ◽  
V. Mahdavi
Keyword(s):  
Dna Binding ◽  
Cell Fate ◽  
Nuclear Dna ◽  
Homeobox Gene ◽  
Cell Types ◽  
Binding Activity ◽  
Specific Gene ◽  
Sequence Specificity ◽  
Protein Species ◽  
Mouse Development

We report the isolation of a cDNA encoding a mammalian homeoprotein related to the Drosophila cut gene product, called Clox, for Cut like homeobox. In addition to the homeodomain, three 73-amino acid repeats, the so-called cut repeats, are also conserved between Cut and the mammalian counterpart described here. This conservation suggests that the cut repeat motif may define a new class of homeoproteins. Both cloned and endogenous Clox proteins are nuclear DNA-binding proteins with very similar sequence specificity. Western blot analysis revealed several distinct Clox protein species in a variety of tissues and cell types. The relative abundance of these proteins is regulated during mouse development and cell differentiation in culture. Interestingly, approximately 180–190 × 10(3) M(r) Clox proteins predominate in early embryos and are upregulated in committed myoblasts and chondrocytes, but downregulated upon terminal differentiation. Clox DNA-binding activity is correlated with the abundance of these proteins. In contrast, larger Clox protein species (approximately 230–250 × 10(3) M(r)) are detected mainly in adult tissues and in terminally differentiated cells. Cotransfection experiments show that Clox proteins can function as repressors of tissue-specific gene transcription. Thus, Clox, like their Drosophila counterparts, are candidate regulators of cell-fate specification in diverse differentiation programs.

scholarly journals Developmental plasticity, cell fate specification and morphogenesis in the early mouse embryo

2014 ◽  
Vol 369 (1657) ◽  
pp. 20130538 ◽  
Author(s):  
Ivan Bedzhov ◽  
Sarah J. L. Graham ◽  
Chuen Yan Leung ◽  
Magdalena Zernicka-Goetz
Keyword(s):  
Cell Fate ◽  
Mouse Embryo ◽  
Developmental Plasticity ◽  
Molecular Mechanisms ◽  
Imaging Techniques ◽  
Cell Signalling ◽  
Three Dimensional ◽  
Early Embryo ◽  
Mammalian Development ◽  
Cell Fate Decisions

A critical point in mammalian development is when the early embryo implants into its mother's uterus. This event has historically been difficult to study due to the fact that it occurs within the maternal tissue and therefore is hidden from view. In this review, we discuss how the mouse embryo is prepared for implantation and the molecular mechanisms involved in directing and coordinating this crucial event. Prior to implantation, the cells of the embryo are specified as precursors of future embryonic and extra-embryonic lineages. These preimplantation cell fate decisions rely on a combination of factors including cell polarity, position and cell–cell signalling and are influenced by the heterogeneity between early embryo cells. At the point of implantation, signalling events between the embryo and mother, and between the embryonic and extraembryonic compartments of the embryo itself, orchestrate a total reorganization of the embryo, coupled with a burst of cell proliferation. New developments in embryo culture and imaging techniques have recently revealed the growth and morphogenesis of the embryo at the time of implantation, leading to a new model for the blastocyst to egg cylinder transition. In this model, pluripotent cells that will give rise to the fetus self-organize into a polarized three-dimensional rosette-like structure that initiates egg cylinder formation.

scholarly journals Distinct mechanisms control genome recognition by p53 at its target genes linked to different cell fates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Marina Farkas ◽  
Hideharu Hashimoto ◽  
Yingtao Bi ◽  
Ramana V. Davuluri ◽  
Lois Resnick-Silverman ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Binding ◽  
Cell Cycle Arrest ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Binding Modes ◽  
Cell Fate Decisions ◽  
Cycle Arrest

AbstractThe tumor suppressor p53 integrates stress response pathways by selectively engaging one of several potential transcriptomes, thereby triggering cell fate decisions (e.g., cell cycle arrest, apoptosis). Foundational to this process is the binding of tetrameric p53 to 20-bp response elements (REs) in the genome (RRRCWWGYYYN0-13RRRCWWGYYY). In general, REs at cell cycle arrest targets (e.g. p21) are of higher affinity than those at apoptosis targets (e.g., BAX). However, the RE sequence code underlying selectivity remains undeciphered. Here, we identify molecular mechanisms mediating p53 binding to high- and low-affinity REs by showing that key determinants of the code are embedded in the DNA shape. We further demonstrate that differences in minor/major groove widths, encoded by G/C or A/T bp content at positions 3, 8, 13, and 18 in the RE, determine distinct p53 DNA-binding modes by inducing different Arg248 and Lys120 conformations and interactions. The predictive capacity of this code was confirmed in vivo using genome editing at the BAX RE to interconvert the DNA-binding modes, transcription pattern, and cell fate outcome.

scholarly journals The Molecular Basis of Specific DNA Binding by the BRG1 AT-hook and Bromodomain

2019 ◽  
Author(s):  
Julio C. Sanchez ◽  
Liyang Zhang ◽  
Stefania Evoli ◽  
Nicholas J. Schnicker ◽  
Maria Nunez-Hernandez ◽  
...  
Keyword(s):  
Dna Binding ◽  
Chromatin Remodeling ◽  
Critical Role ◽  
Binding Pocket ◽  
Structural Basis ◽  
Atpase Subunit ◽  
Baf Complex ◽  
Chromatin Remodeling Complex ◽  
Cancer Mutations ◽  
Dna Specificity

AbstractThe ATP-dependent BAF chromatin remodeling complex plays a critical role in gene regulation by modulating chromatin architecture, and is frequently mutated in cancer. Indeed, subunits of the BAF complex are found to be mutated in >20% of human tumors. The mechanism by which BAF properly navigates chromatin is not fully understood, but is thought to involve a multivalent network of histone and DNA contacts. We previously identified a composite domain in the BRG1 ATPase subunit that is capable of associating with both histones and DNA in a multivalent manner. Mapping the DNA binding pocket revealed that it contains several cancer mutations. Here, we utilize SELEX-seq to identify the DNA specificity of this composite domain and NMR spectroscopy and molecular modelling to determine the structural basis of DNA binding. Finally, we demonstrate that cancer mutations in this domain alter the mode of DNA association.

scholarly journals New mechanism of fibronectin fibril assembly revealed by live imaging and super-resolution microscopy

2020 ◽  
Author(s):  
Darshika Tomer ◽  
Sudipto Munshi ◽  
Brianna E. Alexander ◽  
Brenda French ◽  
Pavan Vedula ◽  
...  
Keyword(s):  
Cell Fate ◽  
Three Dimensional ◽  
Super Resolution ◽  
Live Imaging ◽  
Modular Architecture ◽  
Ecm Remodeling ◽  
Linear Arrays ◽  
Cell Fate Decisions ◽  
Super Resolution Microscopy

AbstractThe regulation of cell fate decisions, morphogenesis, and responses to injury are intimately linked to the process of Fn1 fibrillogenesis. Live imaging and super-resolution microscopy revealed that Fn1 fibrils are not continuous. Instead, Fn1 fibrils arise from nanodomains containing multiple Fn1 dimers. As they move toward cell center, Fn1 nanodomains become organized into linear arrays with a spacing of 130 nm between the nanodomains, with little Fn1 in between; Fn1 nanodomain arrays are resistant to deoxycholate treatment demonstrating that these beaded assemblies are indeed mature Fn1 fibrils. FUD, a bacterial peptide that disrupts Fn1 fibrillogenesis, does not disrupt nanodomain formation; instead, it interferes with the organization of nanodomains into arrays. The nanodomain composition of Fn1 fibrils is observed in multiple contexts: in three-dimensional ECM in vivo, on substrata of different composition and stiffness, and is retained in the absence of cells. The modular architecture of Fn1 fibrils bears important implications for mechanisms of ECM remodeling and signal transduction.

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