scholarly journals Progress and challenges in understanding the regulation and function of p53 dynamics

2021 ◽  
Author(s):  
Zhilin Yang ◽  
Ryan L. Hanson ◽  
Eric Batchelor
Keyword(s):  
Cell Signaling ◽  
Stress Responses ◽  
Molecular Mechanisms ◽  
P53 Expression ◽  
Signaling Systems ◽  
Dynamic Cell ◽  
Dependent Cell ◽  
Cellular Stresses ◽  
And Function ◽  
P53 Network

The dynamics of p53 expression provide a mechanism to increase differentiation between cellular stresses and specificity in appropriate responses. Here, we review recent advances in our understanding of the molecular mechanisms regulating p53 dynamics and the functions of the dynamics in the regulation of p53-dependent cell stress responses. We also compare dynamic encoding in the p53 system with that found in other important cell signaling systems, many of which can interact with the p53 network. Finally, we highlight some of the current challenges in understanding dynamic cell signaling within a larger cellular network context.

scholarly journals Transferring information without distortion

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Steven S Andrews ◽  
Roger Brent ◽  
Gábor Balázsi
Keyword(s):  
Cell Signaling ◽  
Molecular Mechanisms ◽  
Signaling Systems ◽  
Linear Manner

Despite employing diverse molecular mechanisms, many different cell signaling systems avoid losing information by transmitting it in a linear manner.

scholarly journals The human GRB2 and Drosophila Drk genes can functionally replace the Caenorhabditis elegans cell signaling gene sem-5.

1993 ◽  
Vol 4 (11) ◽  
pp. 1175-1188 ◽  
Author(s):  
M J Stern ◽  
L E Marengere ◽  
R J Daly ◽  
E J Lowenstein ◽  
M Kokel ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Cell Signaling ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Sh3 Domains ◽  
Signaling Systems ◽  
Src Homology ◽  
And Function

Mutations in the Caenorhabditis elegans gene sem-5 affect cell signaling processes involved in guiding a class of cell migrations and inducing vulval cell fates. The sem-5 sequence encodes a protein comprised almost exclusively of SH2 and SH3 domains (SH, src homology region) that are found together in many signaling proteins and nonreceptor tyrosine kinases. A human protein, GRB2, was identified by its ability to associate with the activated human epidermal growth factor receptor (hEGFR). The GRB2 and Sem-5 proteins share an identical architecture of their SH2 and SH3 domains and 58% amino acid sequence identity. Here we demonstrate that GRB2 and a Drosophila sem-5-like gene Drk can specifically rescue sem-5 mutants. We also show that Sem-5, like GRB2, can bind to the activated hEGFR in vitro. We further correlate the abilities of several mutant variants of GRB2 and Sem-5 to bind to the hEGFR in vitro with their abilities to functionally replace sem-5 in vivo. These data indicate that GRB2 and Drk are functional homologues of Sem-5 and demonstrate the high degree of conservation of both structure and function between signaling systems throughout evolution.

A Mucin-Specific Protease Enables Molecular and Functional Analysis of Human Cancer-Associated Mucins

2018 ◽  
Author(s):  
Stacy A. Malaker ◽  
Kayvon Pedram ◽  
Michael J. Ferracane ◽  
Elliot C. Woods ◽  
Jessica Kramer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Molecular Mechanisms ◽  
Cultured Cells ◽  
High Resolution Mass Spectrometry ◽  
Human Cancer ◽  
Glycosylation Sites ◽  
Bacterial Protease ◽  
Specific Protease ◽  
To Come ◽  
And Function

<div> <div> <div> <p>Mucins are a class of highly O-glycosylated proteins that are ubiquitously expressed on cellular surfaces and are important for human health, especially in the context of carcinomas. However, the molecular mechanisms by which aberrant mucin structures lead to tumor progression and immune evasion have been slow to come to light, in part because methods for selective mucin degradation are lacking. Here we employ high resolution mass spectrometry, polymer synthesis, and computational peptide docking to demonstrate that a bacterial protease, called StcE, cleaves mucin domains by recognizing a discrete peptide-, glycan-, and secondary structure- based motif. We exploited StcE’s unique properties to map glycosylation sites and structures of purified and recombinant human mucins by mass spectrometry. As well, we found that StcE will digest cancer-associated mucins from cultured cells and from ovarian cancer patient-derived ascites fluid. Finally, using StcE we discovered that Siglec-7, a glyco-immune checkpoint receptor, specifically binds sialomucins as biological ligands, whereas the related Siglec-9 receptor does not. Mucin-specific proteolysis, as exemplified by StcE, is therefore a powerful tool for the study of glycoprotein structure and function and for deorphanizing mucin-binding receptors. </p> </div> </div> </div>

The Anti-Proliferative Activity of Anisosciadone: A New Guaiane Sesquiterpene from Anisosciadium lanatum

2019 ◽  
Vol 19 (9) ◽  
pp. 1114-1119 ◽  
Author(s):  
Ahmed A. Mahmoud ◽  
Wael M. El-Sayed
Keyword(s):  
Anticancer Agents ◽  
Antiproliferative Activity ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Chemical Constituents ◽  
Spectroscopic Techniques ◽  
Significant Activity ◽  
Caspase 9 ◽  
P53 Expression ◽  
Expression And Activity

Background: The increase in cancer rate and the development of resistant tumors require a continuous search for new anticancer agents. Aims: This study aimed to analyze and identify the chemical constituents of Anisosciadium lanatum, and to investigate the antiproliferative activity of the identified constituents against various human cell lines (HepG2, MCF7, HT29, A549, and PC3) along with the possible molecular mechanisms involved. Methods: The structure of the isolated compounds was determined by spectroscopic techniques including HRFABMS, GC-MS, IR, and 400 MHz 1D and 2D NMR analyses (1H, 13C NMR, DEPT, 1H-1H COSY, HMQC, HMBC and NOESY). The antiproliferative activity and IC50 value of the isolated compounds were measured and compared to doxorubicin. Results: A new guaiane sesquiterpene containing a rare epoxide structural element, 10β,11β−epoxy−1α,4β,5β,7αΗ- guaiane-9-one, anisosciadone (1), and stigmasterol (2) have been isolated from the plant. Anisosciadone (1) showed a significant antiproliferative activity against liver, colon, and lung cells only, while stigmasterol (2) had a significant activity against liver, colon, and breast cells. Both 1 and 2 caused no cytotoxicity to normal fibroblasts. Anisosciadone elevated the expression and activity of Caspase 3 as well as p53 expression without affecting Caspase 9 in HepG2 cells. It also caused ~ 50% downregulation in cdk1 expression. Conclusion: Taken together, anisosciadone was specific in action against cancer cells and induced apoptosis in liver cells. It also has a unique feature by elevating the expression and activity of Caspase 3 without affecting the initiator Caspase 9. Therefore, anisosciadone deserves more investigation as a targeted therapy for cancer.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

scholarly journals Maternal Ethanol Exposure Acutely Elevates Src Family Kinase Activity in the Fetal Cortex

2021 ◽  
Author(s):  
Dandan Wang ◽  
Brian W. Howell ◽  
Eric C. Olson
Keyword(s):  
Tyrosine Phosphorylation ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Fetal Brain ◽  
Ethanol Exposure ◽  
Src Family Kinase ◽  
Cortical Cells ◽  
Signaling Systems ◽  
Sustained Reduction ◽  
Reelin Signaling

AbstractFetal alcohol syndrome (FAS) is characterized by disrupted fetal brain development and postnatal cognitive impairment. The targets of alcohol are diverse, and it is not clear whether there are common underlying molecular mechanisms producing these disruptions. Prior work established that acute ethanol exposure causes a transient increase in tyrosine phosphorylation of multiple proteins in cultured embryonic cortical cells. In this study, we show that a similar tyrosine phosphorylation transient occurs in the fetal brain after maternal dosing with ethanol. Using phospho-specific antibodies and immunohistochemistry, we mapped regions of highest tyrosine phosphorylation in the fetal cerebral cortex and found that areas of dendritic and axonal growth showed elevated tyrosine phosphorylation 10 min after maternal ethanol exposure. These were also areas of Src expression and Src family kinase (SFK) activation loop phosphorylation (pY416) expression. Importantly, maternal pretreatment with the SFK inhibitor dasatinib completely prevents both the pY416 increase and the tyrosine phosphorylation response. The phosphorylation response was observed in the perisomatic region and neurites of immature migrating and differentiating primary neurons. Importantly, the initial phosphotyrosine transient (~ 30 min) targets both Src and Dab1, two critical elements in Reelin signaling, a pathway required for normal cortical development. This initial phosphorylation response is followed by sustained reduction in Ser3 phosphorylation of n-cofilin, a critical actin severing protein and an identified downstream effector of Reelin signaling. This biochemical disruption is associated with sustained reduction of F-actin content and disrupted Golgi apparatus morphology in developing cortical neurons. The finding outlines a model in which the initial activation of SFKs by ethanol has the potential to disrupt multiple developmentally important signaling systems for several hours after maternal exposure.

scholarly journals Emerging Data on the Diversity of Molecular Mechanisms Involving C/D snoRNAs

2021 ◽  
Vol 7 (2) ◽  
pp. 30
Author(s):  
Laeya Baldini ◽  
Bruno Charpentier ◽  
Stéphane Labialle
Keyword(s):  
Ribosomal Rna ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Accurate Description ◽  
Small Nucleolar Rnas ◽  
Age Of Maturity ◽  
Non Coding Rnas ◽  
And Function ◽  
Nucleolar Rnas

Box C/D small nucleolar RNAs (C/D snoRNAs) represent an ancient family of small non-coding RNAs that are classically viewed as housekeeping guides for the 2′-O-methylation of ribosomal RNA in Archaea and Eukaryotes. However, an extensive set of studies now argues that they are involved in mechanisms that go well beyond this function. Here, we present these pieces of evidence in light of the current comprehension of the molecular mechanisms that control C/D snoRNA expression and function. From this inventory emerges that an accurate description of these activities at a molecular level is required to let the snoRNA field enter in a second age of maturity.

scholarly journals The Cross-Talk between Mesenchymal Stem Cells and Immune Cells in Tissue Repair and Regeneration

2021 ◽  
Vol 22 (5) ◽  
pp. 2472
Author(s):  
Carl Randall Harrell ◽  
Valentin Djonov ◽  
Vladislav Volarevic
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune Cells ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Multipotent Stem Cells ◽  
Tissue Repair And Regeneration ◽  
Almost All ◽  
And Function

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration.

scholarly journals Expression and function of Smad7 in autoimmune and inflammatory diseases

2021 ◽  
Author(s):  
Yiping Hu ◽  
Juan He ◽  
Lianhua He ◽  
Bihua Xu ◽  
Qingwen Wang
Keyword(s):  
Posttranscriptional Regulation ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Critical Role ◽  
Transforming Growth Factor Β ◽  
Negative Regulator ◽  
Signaling Mechanism ◽  
And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

Sign in / Sign up

Export Citation Format

Share Document