The hypoxic expression of the glucose transporter RAG1 reveals the role of the bHLH transcription factor Sck1 as a novel hypoxic modulator in Kluyveromyces lactis

ABSTRACTGlucose is the preferred nutrient for most living cells and is also a signaling molecule that modulates several cellular processes. Glucose regulates the expression of glucose permease genes in yeasts through signaling pathways dependent on plasma membrane glucose sensors. In the yeast Kluyveromyces lactis, sufficient levels of glucose induction of the low-affinity glucose transporter RAG1 gene also depends on a functional glycolysis, suggesting additional intracellular signaling. We have found that the expression of RAG1 gene is also induced by hypoxia in the presence of glucose, indicating that glucose and oxygen signaling pathways are interconnected. In this study we investigated the molecular mechanisms underlying this crosstalk. By analyzing RAG1 expression in various K. lactis mutants, we found that the bHLH transcriptional activator Sck1 is required for the hypoxic induction of RAG1 gene. The RAG1 promoter region essential for its hypoxic induction was identified by promoter deletion experiments. Taken together, these results show that the RAG1 glucose permease gene is synergistically induced by hypoxia and glucose and highlighted a novel role for the transcriptional activator Sck1 as a key mediator in this mechanism.

Download Full-text

The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽

10.3390/biom9090476 ◽

2019 ◽

Vol 9 (9) ◽

pp. 476 ◽

Cited By ~ 4

Author(s):

Chia-Jung Li ◽

Pei-Yi Chu ◽

Giou-Teng Yiang ◽

Meng-Yu Wu

Keyword(s):

Epithelial Cells ◽

Tumor Progression ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Epithelial Mesenchymal Transition ◽

Transforming Growth Factor Β ◽

Inhibition Of Proliferation ◽

Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

Download Full-text

Interplay between ADP-ribosyltransferases and essential cell signaling pathways controls cellular responses

Cell Discovery ◽

10.1038/s41421-021-00323-9 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Flurina Boehi ◽

Patrick Manetsch ◽

Michael O. Hottiger

Keyword(s):

Cell Signaling ◽

Signaling Pathways ◽

Intracellular Signaling ◽

Cellular Responses ◽

Dynamic Regulation ◽

Post Translational Modifications ◽

Adp Ribosylation ◽

Cellular Processes ◽

Adp Ribosyltransferase ◽

Cell Signaling Pathways

AbstractSignaling cascades provide integrative and interactive frameworks that allow the cell to respond to signals from its environment and/or from within the cell itself. The dynamic regulation of mammalian cell signaling pathways is often modulated by cascades of protein post-translational modifications (PTMs). ADP-ribosylation is a PTM that is catalyzed by ADP-ribosyltransferases and manifests as mono- (MARylation) or poly- (PARylation) ADP-ribosylation depending on the addition of one or multiple ADP-ribose units to protein substrates. ADP-ribosylation has recently emerged as an important cell regulator that impacts a plethora of cellular processes, including many intracellular signaling events. Here, we provide an overview of the interplay between the intracellular diphtheria toxin-like ADP-ribosyltransferase (ARTD) family members and five selected signaling pathways (including NF-κB, JAK/STAT, Wnt-β-catenin, MAPK, PI3K/AKT), which are frequently described to control or to be controlled by ADP-ribosyltransferases and how these interactions impact the cellular responses.

Download Full-text

A mathematical model of metabolic insulin signaling pathways

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00571.2001 ◽

2002 ◽

Vol 283 (5) ◽

pp. E1084-E1101 ◽

Cited By ~ 124

Author(s):

Ahmad R. Sedaghat ◽

Arthur Sherman ◽

Michael J. Quon

Keyword(s):

Experimental Data ◽

Mathematical Model ◽

Insulin Receptor ◽

Signaling Pathways ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Glucose Transporter ◽

Insulin Dose ◽

Model Parameters ◽

Insight Into

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-ζ is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.

Download Full-text

Identification of a new regulation pathway of EGFR and E-cadherin dynamics

10.1101/2020.07.22.215806 ◽

2020 ◽

Author(s):

Veronique Proux-Gillardeaux ◽

Tamara Advedissian ◽

Charlotte Perin ◽

Jean-Christophe Gelly ◽

Mireille Viguier ◽

...

Keyword(s):

Cell Differentiation ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Direct Interaction ◽

Endocytic Pathway ◽

Downstream Signaling ◽

Cellular Processes ◽

Epithelial Homeostasis ◽

Proliferation And Differentiation ◽

E Cadherin

ABSTRACTEGFR plays key roles in multiple cellular processes such as cell differentiation, cell proliferation, migration and epithelia homeostasis. Phosphorylation of the receptor, intracellular signaling and trafficking are major events regulating EGFR functions. Galectin-7, a soluble lectin expressed in epithelia such as the skin, has been shown to be involved in cell differentiation. Through this study we demonstrate that galectin-7 regulates EGFR function by a direct interaction with its extracellular domain hence modifying its downstream signaling and endocytic pathway. From observations in mice we focused on the molecular mechanisms deciphering the glycosylation dependent interaction between EGFR and galectin-7. Interestingly, we also revealed that galectin-7 is a direct binder of both EGFR and E-cadherin bridging them together. Strikingly this study not only deciphers a new molecular mechanism of EGFR regulation but also points out a novel molecular interaction between EGFR and E-cadherin, two major regulators of the balance between proliferation and differentiation.SUMMARYEGFR and E-cadherin are known to interact and to regulate epithelial homeostasis. In this study we unravel in the epidermis a new partner and regulator of EGFR which also binds E-cadherin reciprocally bridging their dynamics and functions.

Download Full-text

The hexokinase gene is required for transcriptional regulation of the glucose transporter gene RAG1 in Kluyveromyces lactis

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.3882-3889.1993 ◽

1993 ◽

Vol 13 (7) ◽

pp. 3882-3889

Author(s):

C Prior ◽

P Mamessier ◽

H Fukuhara ◽

X J Chen ◽

M Wesolowski-Louvel

Keyword(s):

Glucose Transporter ◽

Kinase Activity ◽

Glucose Repression ◽

Kluyveromyces Lactis ◽

Transport Systems ◽

Transporter Gene ◽

Rag1 Gene ◽

Sugar Kinase

The RAG1 gene of Kluyveromyces lactis encodes a low-affinity glucose/fructose transporter. Its transcription is induced by glucose, fructose, and several other sugars. The RAG4, RAG5, and RAG8 genes are trans-acting genes controlling the expression of the RAG1 gene. We report here the characterization of one of these genes, RAG5. The nucleotide sequence of the cloned RAG5 gene indicated that it encodes a protein that is homologous to hexokinases of Saccharomyces cerevisiae. rag5 mutants showed no detectable hexokinase or glucokinase activity, suggesting that the sugar kinase activity encoded by this gene is the only hexokinase in K. lactis. Both high- and low-affinity transport systems of glucose were affected in rag5 mutants. The defect of the low-affinity component was found to be due to a block of transcription of the RAG1 gene by the hexokinase mutation. In vivo complementation of the rag5 mutation by the HXK2 gene of S. cerevisiae and complementation of hxk1 hxk2 mutations of S. cerevisiae by the RAG5 gene showed that RAG5 and HXK2 were equivalent for sugar-phosphorylating activity but that RAG5 could not restore glucose repression in the S. cerevisiae hexokinase mutants.

Download Full-text

Vascular actions of insulin with implications for endothelial dysfunction

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00297.2009 ◽

2009 ◽

Vol 297 (3) ◽

pp. E568-E577 ◽

Cited By ~ 82

Author(s):

Maria Assunta Potenza ◽

Francesco Addabbo ◽

Monica Montagnani

Keyword(s):

Endothelial Dysfunction ◽

Signaling Pathways ◽

Insulin Signaling ◽

Intracellular Signaling ◽

Vascular Function ◽

Molecular Mechanisms ◽

Dynamic Control ◽

Vascular Complications ◽

Short Review ◽

Insulin Resistant

Hemodynamic actions of insulin depend largely on the hormone's ability to stimulate synthesis and release of endothelial mediators, whose balanced activity ensures dynamic control of vascular function. Nitric oxide (NO), endothelin-1 (ET-1), and reactive oxygen species (ROS) are important examples of endothelial mediators with opposing properties on vascular tone, hemostatic processes, and vascular permeability. Reduced NO bioavailability, resulting from either insufficient production or increased degradation of NO, characterizes endothelial dysfunction. In turn, endothelial dysfunction predicts vascular complications of metabolic and hemodynamic disorders. In the cardiovascular system, insulin stimulates the production and release of NO, ET-1, and ROS via activation of distinct intracellular signaling pathways. Under insulin-resistant conditions, increased insulin concentrations and/or impaired insulin-signaling pathways in the vasculature may contribute to imbalance in secretion of endothelial mediators that promote pathogenesis of vascular abnormalities. This short review describes signaling pathways involved in insulin-stimulated release of NO, ROS, and ET-1 and suggests possible molecular mechanisms by which abnormal insulin signaling may contribute to endothelial dysfunction.

Download Full-text

The hexokinase gene is required for transcriptional regulation of the glucose transporter gene RAG1 in Kluyveromyces lactis.

Molecular and Cellular Biology ◽

10.1128/mcb.13.7.3882 ◽

1993 ◽

Vol 13 (7) ◽

pp. 3882-3889 ◽

Cited By ~ 75

Author(s):

C Prior ◽

P Mamessier ◽

H Fukuhara ◽

X J Chen ◽

M Wesolowski-Louvel

Keyword(s):

Glucose Transporter ◽

Kinase Activity ◽

Glucose Repression ◽

Kluyveromyces Lactis ◽

Transport Systems ◽

Transporter Gene ◽

Rag1 Gene ◽

Sugar Kinase

Download Full-text

Control of T lymphocyte fate decisions by PI3K signaling

F1000Research ◽

10.12688/f1000research.26928.1 ◽

2020 ◽

Vol 9 ◽

pp. 1171

Author(s):

Benjamin Murter ◽

Lawrence P. Kane

Keyword(s):

Signaling Pathways ◽

T Lymphocyte ◽

Intracellular Signaling ◽

B Lymphocyte ◽

Lymphocyte Function ◽

Antigen Receptors ◽

Lipid Kinase ◽

Cellular Processes ◽

Intracellular Signaling Pathways ◽

B Lymphocyte Development

Virtually all aspects of T and B lymphocyte development, homeostasis, activation, and effector function are impacted by the interaction of their clonally distributed antigen receptors with antigens encountered in their respective environments. Antigen receptors mediate their effects by modulating intracellular signaling pathways that ultimately impinge on the cytoskeleton, bioenergetic pathways, transcription, and translation. Although these signaling pathways are rather well described at this point, especially those steps that are most receptor-proximal, how such pathways contribute to more quantitative aspects of lymphocyte function is still being elucidated. One of the signaling pathways that appears to be involved in this “tuning” process is controlled by the lipid kinase PI3K. Here we review recent key findings regarding both the triggering/enhancement of PI3K signals (via BCAP and ICOS) as well as their regulation (via PIK3IP1 and PHLPP) and how these signals integrate and determine cellular processes. Lymphocytes display tremendous functional plasticity, adjusting their metabolism and gene expression programs to specific conditions depending on their tissue of residence and the nature of the infectious threat to which they are responding. We give an overview of recent findings that have contributed to this model, with a focus on T cells, including what has been learned from patients with gain-of-function mutations in PI3K as well as lessons from cancer immunotherapy approaches.

Download Full-text

Notch Signaling Regulation in Autoinflammatory Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms21228847 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8847

Author(s):

Rossella Gratton ◽

Paola Maura Tricarico ◽

Adamo Pio d'Adamo ◽

Anna Monica Bianco ◽

Ronald Moura ◽

...

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Target Genes ◽

Notch Pathway ◽

Autoinflammatory Diseases ◽

Cellular Processes ◽

Core Components

Notch pathway is a highly conserved intracellular signaling route that modulates a vast variety of cellular processes including proliferation, differentiation, migration, cell fate and death. Recently, the presence of a strict crosstalk between Notch signaling and inflammation has been described, although the precise molecular mechanisms underlying this interplay have not yet been fully unravelled. Disruptions in Notch cascade, due both to direct mutations and/or to an altered regulation in the core components of Notch signaling, might lead to hypo- or hyperactivation of Notch target genes and signaling molecules, ultimately contributing to the onset of autoinflammatory diseases. To date, alterations in Notch signaling have been reported as associated with three autoinflammatory disorders, therefore, suggesting a possible role of Notch in the pathogenesis of the following diseases: hidradenitis suppurativa (HS), Behçet disease (BD), and giant cell arteritis (GCA). In this review, we aim at better characterizing the interplay between Notch and autoinflammatory diseases, trying to identify the role of this signaling route in the context of these disorders.

Download Full-text

Transcriptomic analysis of tobacco-flavored E-cigarette and menthol-flavored E-cigarette exposure in the human middle ear

Scientific Reports ◽

10.1038/s41598-020-77816-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jae-Jun Song ◽

Yoon Young Go ◽

Jong Kyou Lee ◽

Bum Sang Lee ◽

Su-Kyoung Park ◽

...

Keyword(s):

Signaling Pathways ◽

Differentially Expressed Genes ◽

Middle Ear ◽

Differentially Expressed ◽

Heme Oxygenase 1 ◽

Bhlh Transcription Factor ◽

Prostaglandin Endoperoxide ◽

Cellular Processes ◽

Prostaglandin Endoperoxide Synthase ◽

Human Middle Ear

AbstractElectronic cigarettes (e-cigarettes) are the most widely used electronic nicotine delivery systems and are designed to imitate smoking and aid in smoking cessation. Although the number of e-cigarette users is increasing rapidly, especially among young adults and adolescents, the potential health impacts and biologic effects of e-cigarettes still need to be elucidated. Our previous study demonstrated the cytotoxic effects of electronic liquids (e-liquids) in a human middle ear epithelial cell (HMEEC-1) line, which were affected by the manufacturer and flavoring agents regardless of the presence of nicotine. In this study, we aimed to evaluate the gene expression profile and identify potential molecular modulator genes and pathways in HMEEC-1 exposed to two different e-liquids (tobacco- and menthol-flavored). HMEEC-1 was exposed to e-liquids, and RNA sequencing, functional analysis, and pathway analysis were conducted to identify the resultant transcriptomic changes. A total of 843 genes were differentially expressed following exposure to the tobacco-flavored e-liquid, among which 262 genes were upregulated and 581 were downregulated. Upon exposure to the menthol-flavored e-liquid, a total of 589 genes were differentially expressed, among which 228 genes were upregulated and 361 were downregulated. Among the signaling pathways associated with the differentially expressed genes mediated by tobacco-flavored e-liquid exposure, several key molecular genes were identified, including IL6 (interleukin 6), PTGS2 (prostaglandin-endoperoxide synthase 2), CXCL8 (C-X-C motif chemokine ligand 8), JUN (Jun proto-oncogene), FOS (Fos proto-oncogene), and TP53 (tumor protein 53). Under menthol-flavored e-liquid treatment, MMP9 (matrix metallopeptidase 9), PTGS2 (prostaglandin-endoperoxide synthase 2), MYC (MYC proto-oncogene, bHLH transcription factor), HMOX1 (heme oxygenase 1), NOS3 (nitric oxide synthase 3), and CAV1 (caveolin 1) were predicted as key genes. In addition, we identified related cellular processes, including inflammatory responses, oxidative stress and carcinogenesis, under exposure to tobacco- and menthol-flavored e-liquids. We identified differentially expressed genes and related cellular processes and gene signaling pathways after e-cigarette exposure in human middle ear cells. These findings may provide useful evidence for understanding the effect of e-cigarette exposure.

Download Full-text