The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽  
2021 ◽  
pp. 273250162110243
Author(s):  
Mikhail Pakvasa ◽  
Andrew B. Tucker ◽  
Timothy Shen ◽  
Tong-Chuan He ◽  
Russell R. Reid
Keyword(s):  
Intracellular Signaling ◽  
Limb Development ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Craniofacial Development ◽  
Signaling Cascade ◽  
Signaling Mechanisms ◽  
Intracellular Signaling Cascade ◽  
And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

scholarly journals The Complicated Body in Motion: Rediscovering the Mechanical Stimulations in Cell Models of Human Disease

2019 ◽  
Author(s):  
Tzyy-Yue Wong ◽  
Yu-Kai Tseng ◽  
Tung-Chen Yeh ◽  
Rong-Chang Jhong ◽  
Yue-Fang Wang ◽  
...  
Keyword(s):  
Mechanical Stimulation ◽  
Intracellular Signaling ◽  
The Body ◽  
Signaling Cascade ◽  
Physical Injury ◽  
Cell Models ◽  
Physical Stimulation ◽  
Intracellular Signaling Cascade ◽  
The Mind

Thought runs through the mind like blood runs through our body to keep us alive. Like the mind, the body does not stay inert and is in constant motion. Not a single cell in our body is left inert unless cell is under stress or dying. These scenarios are reflected upon when a person is sick, the person lies in bed with less movement; however, is active when the person is healthy. The topic of mechanical stimulation has emerged due to the increasing understanding of the physical stimulations we face each day. Further understanding of the mechanically-regulated mechanism can help us explore the pathological events in a disease. Here, we reviewed the role of sensory proteins in pathological events that are observed in cardiomyopathy, cancer, respiratory, renal, obesity, genetics, physical injury and bacterial infection. Taken together, sensory proteins are mechanically-activated which assist reception of external physical stimulation and convert into biochemical to trigger intracellular signaling cascade.

scholarly journals miR-21 is upregulated, promoting fibrosis and blocking G2/M in irradiated rat cardiac fibroblasts

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e10502
Author(s):  
Huan Guo ◽  
Xinke Zhao ◽  
Haixiang Su ◽  
Chengxu Ma ◽  
Kai Liu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Differentially Expressed Gene ◽  
Stem Loop ◽  
Cardiac Morbidity ◽  
Increased Risk ◽  
And Function

Background Radiation exposure of the thorax is associated with a greatly increased risk of cardiac morbidity and mortality even after several decades of advancement in the field. Although many studies have demonstrated the damaging influence of ionizing radiation on cardiac fibroblast (CF) structure and function, myocardial fibrosis, the molecular mechanism behind this damage is not well understood. miR-21, a small microRNA, promotes the activation of CFs, leading to cardiac fibrosis. miR-21 is overexpressed after irradiation; however, the relationship between increased miR-21 and myocardial fibrosis after irradiation is unclear. This study was conducted to investigate gene expression after radiation-induced CF damage and the role of miR-21 in this process in rats. Methods We sequenced irradiated rat CFs and performed weighted correlation network analysis (WGCNA) combined with differentially expressed gene (DEG) analysis to observe the effect on the expression profile of CF genes after radiation. Results DEG analysis showed that the degree of gene changes increased with the radiation dose. WGCNA revealed three module eigengenes (MEs) associated with 8.5-Gy-radiation—the Yellow, Brown, Blue modules. The three module eigengenes were related to apoptosis, G2/M phase, and cell death and S phase, respectively. By blocking with the cardiac fibrosis miRNA miR-21, we found that miR-21 was associated with G2/M blockade in the cell cycle and was mainly involved in regulating extracellular matrix-related genes, including Grem1, Clu, Gdf15, Ccl7, and Cxcl1. Stem-loop quantitative real-time PCR was performed to verify the expression of these genes. Five genes showed higher expression after 8.5 Gy-radiation in CFs. The target genes of miR-21 predicted online were Gdf15 and Rsad2, which showed much higher expression after treatment with antagomir-miR-21 in 8.5-Gy-irradiated CFs. Thus, miR-21 may play the role of fibrosis and G2/M blockade in regulating Grem1, Clu, Gdf15, Ccl7, Cxcl1, and Rsad2 post-irradiation.

scholarly journals Phosphoproteomic quantitation and causal analysis reveal pathways in GPVI/ITAM-mediated platelet activation programs

Blood ◽  
2020 ◽  
Vol 136 (20) ◽  
pp. 2346-2358 ◽  
Author(s):  
Özgün Babur ◽  
Alexander R. Melrose ◽  
Jennifer M. Cunliffe ◽  
John Klimek ◽  
Jiaqing Pang ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Intracellular Signaling ◽  
Vascular Inflammation ◽  
Functional Screening ◽  
Tandem Mass ◽  
Rab Gtpases ◽  
Platelet Surface ◽  
Form And Function ◽  
Signaling Mechanisms ◽  
And Function

Abstract Platelets engage cues of pending vascular injury through coordinated adhesion, secretion, and aggregation responses. These rapid, progressive changes in platelet form and function are orchestrated downstream of specific receptors on the platelet surface and through intracellular signaling mechanisms that remain systematically undefined. This study brings together cell physiological and phosphoproteomics methods to profile signaling mechanisms downstream of the immunotyrosine activation motif (ITAM) platelet collagen receptor GPVI. Peptide tandem mass tag (TMT) labeling, sample multiplexing, synchronous precursor selection (SPS), and triple stage tandem mass spectrometry (MS3) detected >3000 significant (false discovery rate < 0.05) phosphorylation events on >1300 proteins over conditions initiating and progressing GPVI-mediated platelet activation. With literature-guided causal inference tools, >300 site-specific signaling relations were mapped from phosphoproteomics data among key and emerging GPVI effectors (ie, FcRγ, Syk, PLCγ2, PKCδ, DAPP1). Through signaling validation studies and functional screening, other less-characterized targets were also considered within the context of GPVI/ITAM pathways, including Ras/MAPK axis proteins (ie, KSR1, SOS1, STAT1, Hsp27). Highly regulated GPVI/ITAM targets out of context of curated knowledge were also illuminated, including a system of >40 Rab GTPases and associated regulatory proteins, where GPVI-mediated Rab7 S72 phosphorylation and endolysosomal maturation were blocked by TAK1 inhibition. In addition to serving as a model for generating and testing hypotheses from omics datasets, this study puts forth a means to identify hemostatic effectors, biomarkers, and therapeutic targets relevant to thrombosis, vascular inflammation, and other platelet-associated disease states.

scholarly journals THE ROLE OF SYNAPSIN I IN INTRACELLULAR SIGNALING MECHANISMS UNDERLIES EXERCISE-INDUCED IMPROVEMENT IN SOCIAL MEMORY: A SYSTEMATIC REVIEW

2017 ◽  
Vol 10 (9) ◽  
pp. 88
Author(s):  
Ria Margiana ◽  
Akmal Primadian Suprapto
Keyword(s):  
Cell Signaling ◽  
Intracellular Signaling ◽  
Laboratory Experiments ◽  
Biological Function ◽  
Social Memory ◽  
Synapsin I ◽  
Signaling Mechanism ◽  
Signaling Mechanisms ◽  
Exercise Induced

  Objective: Intracellular signaling mechanism is an important biological function, as scholars continue to seek new ways of improving social memory. Researchers have conducted several studies on the role of synapsin I in intracellular signaling mechanism. This study assessed the empirical evidence that shows the role of synapsin I in intracellular signaling mechanism with the aim of achieving exercise-induced improvement in social memory.Methods: Nine previously conducted researches were reviewed in this paper. The included studies were controlled laboratory experiments involving mice as the subjects.Results: Although the studies included were done in different timelines, the researchers agreed in unison that synapsin I plays a crucial role in cell signaling. The outcome of the practical studies was vital in understanding function and physiology of human cells, which is fundamental in science and human anatomy.Conclusion: In particular, the findings shows how exercise can improve social memory by triggering the intracellular signaling mechanism. The limited number of studies addressing the topic of intracellular cell signaling suggests that more study is needed to provide more evidence on the issue.

scholarly journals Cochaperone Mzb1 is a key effector of Blimp1 in plasma cell differentiation and β1-integrin function

2018 ◽  
Vol 115 (41) ◽  
pp. E9630-E9639 ◽  
Author(s):  
Virginia Andreani ◽  
Senthilkumar Ramamoorthy ◽  
Abhinav Pandey ◽  
Ekaterina Lupar ◽  
Stephen L. Nutt ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Target Genes ◽  
Β1 Integrin ◽  
Plasma Cell Differentiation ◽  
And Migration ◽  
And Function ◽  
Antibody Secreting Cells

Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 cochaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells. By analyzing Mzb1−/−Prdm1+/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of antibody-secreting cells in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes. In addition, we find that Mzb1−/− plasmablasts show a reduced activation of β1-integrin, which contributes to the impaired plasmablast differentiation and migration of antibody-secreting cells to the bone marrow. Thus, Mzb1 function is required for multiple aspects of plasma cell differentiation.

scholarly journals The Role of Phosphotyrosine Signaling Pathway in Parotid Gland Proliferation and Function

1995 ◽  
Vol 6 (2) ◽  
pp. 119-131 ◽  
Author(s):  
K.R. Purushotham ◽  
M.G. Humphreys-Beher
Keyword(s):  
Salivary Glands ◽  
Tyrosine Kinases ◽  
Intracellular Signaling ◽  
Potential Role ◽  
Biological Processes ◽  
Secretory Function ◽  
Phosphotyrosine Signaling ◽  
And Function ◽  
Active Proliferation

Tyrosine phosphorylation and the intracellular signaling processes associated with it have been the focus of intense study due to its importance in the regulation of biological processes as diverse as cell proliferation and cell differentiation. While much of what we now understand has been derived from the study of cell lines and tumor cells, the salivary glands provide a model to examine the effects of tyrosine kinases and tyrosine phosphatases in a normal differentiated tissue. This review will focus, therefore, on the role tyrosine kinases and phosphatases play in inducing the transition from stasis to active proliferation and their potential role in mediating secretory function of the salivary glands.

scholarly journals Role of Sp1 in insulin regulation of gene expression

2002 ◽  
Vol 29 (3) ◽  
pp. 265-279 ◽  
Author(s):  
SL Samson ◽  
NC Wong
Keyword(s):  
Intracellular Signaling ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Protein A ◽  
Peptide Hormone ◽  
Fine Tuning ◽  
Signaling Cascades ◽  
Specific Interest ◽  
Extracellular Signals

Sp1 is a ubiquitous nuclear factor that plays a key role in maintaining basal transcription of 'house-keeping' genes. However, recent evidence points to a more important function for Sp1 in mediating 'cross-talk' between selected signaling cascades to regulate the target genes that respond to these pathways. The role of Sp1 in mediating the actions of the peptide hormone insulin is of specific interest and serves as a model for detailing effects of intracellular signaling on Sp1 activity. This review summarizes studies suggesting that changes in Sp1 phosphorylation provide one potential mechanism for manipulating activity of this protein. A growing body of evidence reveals that the DNA binding and transcription activity of Sp1 may increase or decrease in response to changes in phosphorylation. This enables 'fine-tuning' of Sp1 activity for regulation of gene transcription. Several mechanisms exist by which Sp1 alters gene activity in response to insulin. These include independent Sp1 activity as well as collaboration or competition with others factors. This review points to an ever-increasing role for Sp1 in regulating the transcription of genes in response to extracellular signals such as insulin.

scholarly journals Ecology and molecular targets of hypermutation in the global microbiome

2020 ◽  
Author(s):  
Simon Roux ◽  
Blair G. Paul ◽  
Sarah C. Bagby ◽  
Michelle A. Allen ◽  
Graeme Attwood ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Target Genes ◽  
Distinct Type ◽  
Raw Material ◽  
Read Mapping ◽  
A Genome ◽  
And Function ◽  
Natural Communities ◽  
Cellular Genome

AbstractChanges in the sequence of an organism’s genome, i.e. mutations, are the raw material of evolution1. The frequency and location of mutations can be constrained by specific molecular mechanisms, such as Diversity-generating retroelements (DGRs)2–4. DGRs introduce mutations in specific target genes, and were characterized from several cultivated bacteria and bacteriophages2. Whilst a larger diversity of DGR loci has been identified in genomic data from environmental samples, i.e. metagenomes, the ecological role of these DGRs and their associated evolutionary drivers remain poorly understood5–7. Here we built and analyzed an extensive dataset of >30,000 metagenome-derived DGRs, and determine that DGRs have a single evolutionary origin and a universal bias towards adenine mutations. We further identified six major lineages of DGRs, each associated with a specific ecological niche defined as a genome type, i.e. whether the DGR is encoded on a viral or cellular genome, a limited set of taxa and environments, and a distinct type of target. Finally, we leverage read mapping and metagenomic time series to demonstrate that DGRs are consistently and broadly active, and responsible for >10% of all amino acid changes in some organisms at a conservative estimate. Overall, these results highlight the strong constraints under which DGRs diversify and expand, and elucidate several distinct roles these elements play in natural communities and in shaping microbial community structure and function in our environment.

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