scholarly journals Emerging roles for non-selenium containing ER-resident glutathione peroxidases in cell signaling and disease

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Katalin Buday ◽  
Marcus Conrad
Keyword(s):  
Cell Fate ◽  
Metabolic Diseases ◽  
Endotoxic Shock ◽  
Redox Control ◽  
Cellular Functions ◽  
Redox Systems ◽  
Cellular Redox ◽  
Cell Fate Decisions ◽  
Cellular Processes ◽  
Glutathione Peroxidases

AbstractMaintenance of cellular redox control is pivotal for normal cellular functions and cell fate decisions including cell death. Among the key cellular redox systems in mammals, the glutathione peroxidase (GPX) family of proteins is the largest conferring multifaceted functions and affecting virtually all cellular processes. The endoplasmic reticulum (ER)-resident GPXs, designated as GPX7 and GPX8, are the most recently added members of this family of enzymes. Recent studies have provided exciting insights how both enzymes support critical processes of the ER including oxidative protein folding, maintenance of ER redox control by eliminating H2O2, and preventing palmitic acid-induced lipotoxicity. Consequently, numerous pathological conditions, such as neurodegeneration, cancer and metabolic diseases have been linked with altered GPX7 and GPX8 expression. Studies in mice have demonstrated that loss of GPX7 leads to increased differentiation of preadipocytes, increased tumorigenesis and shortened lifespan. By contrast, GPX8 deficiency in mice results in enhanced caspase-4/11 activation and increased endotoxic shock in colitis model. With the increasing recognition that both types of enzymes are dysregulated in various tumor entities in man, we deem a review of the emerging roles played by GPX7 and GPX8 in health and disease development timely and appropriate.

Dynamic Mechanical Properties Control Adult Stem Cell Fate

2012 ◽  
Author(s):  
Murat Guvendiren ◽  
Jason A. Burdick
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Adult Stem Cell ◽  
Dynamic Mechanical Properties ◽  
Cellular Functions ◽  
Cellular Processes ◽  
Proliferation And Differentiation ◽  
Important Field ◽  
Control Adult

Stem cells respond to many microenvironmental cues towards their decisions to spread, migrate, and differentiate and these cues can be incorporated into materials for regenerative medicine.1 In the last decade, matrix stiffness alone has been implicated in regulating cellular functions such as migration, proliferation and differentiation. With this in mind, a variety of natural and synthetic polymer systems were used in vitro to mimic the elasticity of native tissues. Despite helping to develop this important field and gather valuable information, these substrates are primarily static and lack the dynamic nature that is observed during many cellular processes such as development, fibrosis and cancer. Thus, it is of great interest to temporally manipulate matrix elasticity in vitro to better understand and develop strategies to control these biological processes. In this work, we utilize a sequential crosslinking approach (initial gelation via addition reaction, secondary crosslinking through light-mediated radical polymerization) to fabricate hydrogel substrates that stiffen (e.g., ∼3 to 30 kPa) either immediately or at later times and in the presence of cells. We demonstrate the utility of this technique by investigating the short-term (several minutes to hours) and long-term (several days to weeks) stem cell response to dynamic stiffening

The anti-oxidant and pro-oxidant dichotomy of Bcl-2

2016 ◽  
Vol 397 (7) ◽  
pp. 585-593 ◽  
Author(s):  
Yi Hui Yee ◽  
Stephen Jun Fei Chong ◽  
Shazib Pervaiz
Keyword(s):  
Cell Fate ◽  
Wide Spectrum ◽  
Survival Function ◽  
Short Review ◽  
Redox Status ◽  
Aberrant Expression ◽  
Cellular Redox ◽  
Cell Fate Decisions ◽  
Anti Oxidant ◽  
Novel Therapeutic Strategies

Abstract Across a wide spectrum of cellular redox status, there emerges a dichotomy of responses in terms of cell survival/proliferation and cell death. Of note, there is emerging evidence that the anti-apoptotic protein, Bcl-2, in addition to its conventional activity of titrating the pro-apoptotic effects of proteins such as Bax and Bak at the mitochondria, also impacts cell fate decisions via modulating cellular redox metabolism. In this regard, both pro- and anti-oxidant effects of Bcl-2 overexpression have been described under different conditions and cellular contexts. In this short review, we attempt to analyze existing observations and present a probable explanation for the seemingly conflicting redox regulating activity of Bcl-2 from the standpoint of its pro-survival function. The consequential effect(s) of the dual redox functions of Bcl-2 are also discussed, particularly from the viewpoint of developing novel therapeutic strategies against cancers rendered refractory due to the aberrant expression of Bcl-2.

scholarly journals Accurate Prediction of Kinase-Substrate Networks Using Knowledge Graphs

2019 ◽  
Author(s):  
Vít Nováček ◽  
Gavin McGauran ◽  
David Matallanas ◽  
Adrián Vallejo Blanco ◽  
Piero Conca ◽  
...  
Keyword(s):  
Cell Fate ◽  
Large Scale ◽  
Conceptual Approach ◽  
Kinase Substrate ◽  
Biochemical Processes ◽  
Cell Fate Decisions ◽  
Cellular Processes ◽  
Robust Model ◽  
Vital Cell ◽  
Knowledge Graphs

AbstractPhosphorylation of specific substrates by protein kinases is a key control mechanism for vital cell-fate decisions and other cellular processes. However, discovering specific kinase-substrate relationships is timeconsuming and often rather serendipitous. Computational predictions alleviate these challenges, but the current approaches suffer from limitations like restricted kinome coverage and inaccuracy. They also typically utilise only local features without reflecting broader interaction context. To address these limitations, we have developed an alternative predictive model. It uses statistical relational learning on top of phosphorylation networks interpreted as knowledge graphs, a simple yet robust model for representing networked knowledge. Compared to a representative selection of six existing systems, our model has the highest kinome coverage and produces biologically valid high-confidence predictions not possible with the other tools. Specifically, we have experimentally validated predictions of previously unknown phosphorylations by the LATS1, AKT1, PKA and MST2 kinases in human. Thus, our tool is useful for focusing phosphoproteomic experiments, and facilitates the discovery of new phosphorylation reactions. Our model can be accessed publicly via an easy-to-use web interface (LinkPhinder).Author SummaryLinkPhinder is a new approach to prediction of protein signalling networks based on kinase-substrate relationships that outperforms existing approaches. Phosphorylation networks govern virtually all fundamental biochemical processes in cells, and thus have moved into the centre of interest in biology, medicine and drug development. Fundamentally different from current approaches, LinkPhinder is inherently network-based and makes use of the most recent AI de-velopments. We represent existing phosphorylation data as knowledge graphs, a format for large-scale and robust knowledge representation. Training a link prediction model on such a structure leads to novel, biologically valid phosphorylation network predictions that cannot be made with competing tools. Thus our new conceptual approach can lead to establishing a new niche of AI applications in computational biology.

scholarly journals Accurate prediction of kinase-substrate networks using knowledge graphs

2020 ◽  
Vol 16 (12) ◽  
pp. e1007578
Author(s):  
Vít Nováček ◽  
Gavin McGauran ◽  
David Matallanas ◽  
Adrián Vallejo Blanco ◽  
Piero Conca ◽  
...  
Keyword(s):  
Cell Fate ◽  
Web Interface ◽  
Kinase Substrate ◽  
Cell Fate Decisions ◽  
Cellular Processes ◽  
Robust Model ◽  
Vital Cell ◽  
Knowledge Graphs ◽  
Computational Predictions ◽  
Selection Of

Phosphorylation of specific substrates by protein kinases is a key control mechanism for vital cell-fate decisions and other cellular processes. However, discovering specific kinase-substrate relationships is time-consuming and often rather serendipitous. Computational predictions alleviate these challenges, but the current approaches suffer from limitations like restricted kinome coverage and inaccuracy. They also typically utilise only local features without reflecting broader interaction context. To address these limitations, we have developed an alternative predictive model. It uses statistical relational learning on top of phosphorylation networks interpreted as knowledge graphs, a simple yet robust model for representing networked knowledge. Compared to a representative selection of six existing systems, our model has the highest kinome coverage and produces biologically valid high-confidence predictions not possible with the other tools. Specifically, we have experimentally validated predictions of previously unknown phosphorylations by the LATS1, AKT1, PKA and MST2 kinases in human. Thus, our tool is useful for focusing phosphoproteomic experiments, and facilitates the discovery of new phosphorylation reactions. Our model can be accessed publicly via an easy-to-use web interface (LinkPhinder).

scholarly journals The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

2021 ◽  
Vol 22 (10) ◽  
pp. 5209
Author(s):  
Stine F. Pedersen ◽  
Mette Flinck ◽  
Luis A. Pardo
Keyword(s):  
Ion Transport ◽  
Cell Fate ◽  
Mitochondrial Function ◽  
Ion Homeostasis ◽  
Reciprocal Relationship ◽  
Cancer Development ◽  
Cellular Functions ◽  
Atp Production ◽  
Cell Fate Decisions

Transport of ions and nutrients is a core mitochondrial function, without which there would be no mitochondrial metabolism and ATP production. Both ion homeostasis and mitochondrial phenotype undergo pervasive changes during cancer development, and both play key roles in driving the malignancy. However, the link between these events has been largely ignored. This review comprehensively summarizes and critically discusses the role of the reciprocal relationship between ion transport and mitochondria in crucial cellular functions, including metabolism, signaling, and cell fate decisions. We focus on Ca2+, H+, and K+, which play essential and highly interconnected roles in mitochondrial function and are profoundly dysregulated in cancer. We describe the transport and roles of these ions in normal mitochondria, summarize the changes occurring during cancer development, and discuss how they might impact tumorigenesis.

scholarly journals The influence of mitochondrial-directed regulation of Wnt signaling on tumorigenesis

2020 ◽  
Vol 8 (3) ◽  
pp. 215-223 ◽  
Author(s):  
Yaritza Delgado-Deida ◽  
Kibrom M Alula ◽  
Arianne L Theiss
Keyword(s):  
Wnt Signaling ◽  
Cell Fate ◽  
Therapeutic Strategy ◽  
Wnt Signaling Pathway ◽  
Cellular Functions ◽  
Additional Mechanism ◽  
Cell Fate Decisions ◽  
Stem Cell Maintenance ◽  
Feedforward Loop ◽  
Mitochondrial Alterations

Abstract Mitochondria are dynamic organelles that play a key role in integrating cellular signaling. Mitochondrial alterations are evident in all stages of tumorigenesis and targeting mitochondrial pathways has emerged as an anticancer therapeutic strategy. The Wnt-signaling pathway regulates many fundamental cellular functions such as proliferation, survival, migration, stem-cell maintenance, and mitochondrial metabolism and dynamics. Emerging evidence demonstrates that mitochondrial-induced regulation of Wnt signaling provides an additional mechanism to influence cell-fate decisions. Crosstalk between mitochondria and Wnt signaling presents a feedforward loop in which Wnt activation regulates mitochondrial function that, in turn, drives Wnt signaling. In this mini-review, we will discuss the recent evidence revealing the mitochondrial control of Wnt signaling and its implications for tumorigenesis and anticancer therapeutic targeting.

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