scholarly journals Estrogen receptors promote NSCLC progression by modulating the membrane receptor signaling network: a systems biology perspective

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Xiujuan Gao ◽  
Yue Cai ◽  
Zhuo Wang ◽  
Wenjuan He ◽  
Sisi Cao ◽  
...  
Keyword(s):  
Systems Biology ◽  
Estrogen Receptors ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Signaling Network ◽  
Membrane Receptor ◽  
Receptor Signaling ◽  
Molecular Signaling ◽  
Cell Behaviors ◽  
Cancer Systems Biology

Abstract Background Estrogen receptors (ERs) are thought to play an important role in non-small cell lung cancer (NSCLC). However, the effect of ERs in NSCLC is still controversial and needs further investigation. A new consideration is that ERs may affect NSCLC progression through complicated molecular signaling networks rather than individual targets. Therefore, this study aims to explore the effect of ERs in NSCLC from the perspective of cancer systems biology. Methods The gene expression profile of NSCLC samples in TCGA dataset was analyzed by bioinformatics method. Variations of cell behaviors and protein expression were detected in vitro. The kinetic process of molecular signaling network was illustrated by a systemic computational model. At last, immunohistochemical (IHC) and survival analysis was applied to evaluate the clinical relevance and prognostic effect of key receptors in NSCLC. Results Bioinformatics analysis revealed that ERs might affect many cancer-related molecular events and pathways in NSCLC, particularly membrane receptor activation and signal transduction, which might ultimately lead to changes in cell behaviors. Experimental results confirmed that ERs could regulate cell behaviors including cell proliferation, apoptosis, invasion and migration; ERs also regulated the expression or activation of key members in membrane receptor signaling pathways such as epidermal growth factor receptor (EGFR), Notch1 and Glycogen synthase kinase-3β/β-Catenin (GSK3β/β-Catenin) pathways. Modeling results illustrated that the promotive effect of ERs in NSCLC was implemented by modulating the signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways; ERs maintained and enhanced the output of oncogenic signals by adding redundant and positive-feedback paths into the network. IHC results echoed that high expression of ERs, EGFR and Notch1 had a synergistic effect on poor prognosis of advanced NSCLC. Conclusions This study indicated that ERs were likely to promote NSCLC progression by modulating the integrated membrane receptor signaling network composed of EGFR, Notch1 and GSK3β/β-Catenin pathways and then affecting tumor cell behaviors. It also complemented the molecular mechanisms underlying the progression of NSCLC and provided new opportunities for optimizing therapeutic scheme of NSCLC.

scholarly journals The Role of Androgen Receptor Signaling in Ovarian Cancer

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 176 ◽  
Author(s):  
Taichi Mizushima ◽  
Hiroshi Miyamoto
Keyword(s):  
Ovarian Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Receptor Signaling ◽  
Therapeutic Approaches ◽  
Androgen Receptor Signaling ◽  
Ovarian Carcinogenesis ◽  
Androgen Receptor Activity

Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This review summarizes and discusses the available data indicating the involvement of androgens as well as androgen receptor and related signals in ovarian carcinogenesis and cancer growth. Although the underlying molecular mechanisms for androgen receptor functions in ovarian cancer remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches, via modulation of androgen receptor activity, against ovarian cancer. Indeed, several clinical trials have been conducted to determine the efficacy of androgen deprivation therapy in patients with ovarian cancer.

scholarly journals Skeletal Muscle Atrophy: Discovery of Mechanisms and Potential Therapies

Physiology ◽  
2019 ◽  
Vol 34 (4) ◽  
pp. 232-239 ◽  
Author(s):  
Scott M. Ebert ◽  
Asma Al-Zougbi ◽  
Sue C. Bodine ◽  
Christopher M. Adams
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Signaling Network ◽  
Skeletal Muscle Atrophy ◽  
Molecular Signaling ◽  
Molecular Signaling Network

Skeletal muscle atrophy proceeds through a complex molecular signaling network that is just beginning to be understood. Here, we discuss examples of recently identified molecular mechanisms of muscle atrophy and how they highlight an immense need and opportunity for focused biochemical investigations and further unbiased discovery work.

scholarly journals G-1-Activated Membrane Estrogen Receptors Mediate Increased Contractility of the Human Myometrium

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2448-2455 ◽  
Author(s):  
K. Maiti ◽  
J. W. Paul ◽  
M. Read ◽  
E. C. Chan ◽  
S. C. Riley ◽  
...  
Keyword(s):  
Estrogen Receptors ◽  
Receptor Agonist ◽  
Contractile Response ◽  
Small Heat Shock Protein ◽  
Receptor Activation ◽  
Membrane Receptor ◽  
Human Myometrium ◽  
Uterine Contractility ◽  
Rt Pcr ◽  
G Protein Coupled

Estrogens are key mediators of increased uterine contractility at labor. We sought to determine whether membrane-associated estrogen receptors, such as the recently described seven-transmembrane receptor G protein-coupled receptor 30 (GPR30), mediated some of this effect. Using human myometrium obtained at term cesarean section before or after the onset of labor, we demonstrated the presence of GPR30 mRNA and protein using quantitative RT-PCR and Western blotting. GPR30 receptor was localized to the cell membrane and often colocalized with calveolin-1. Using the specific estrogen membrane receptor agonist G-1 and myometrial explants, we showed that membrane receptor activation led to phosphorylation of MAPK and the actin-modifying small heat shock protein 27. Using myometrial strips incubated with G-1 or vehicle we demonstrated that estrogen membrane receptor activation increased the myometrial contractile response to oxytocin. These data suggest that activation of the plasma membrane estrogen receptor GPR30 likely participates in the physiology of the human myometrium during pregnancy and identifies it as a potential target to modify uterine activity.

scholarly journals Neurexins regulate presynaptic GABAB-receptors at central synapses

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Fujun Luo ◽  
Alessandra Sclip ◽  
Sean Merrill ◽  
Thomas C. Südhof
Keyword(s):  
Active Zone ◽  
Neurotransmitter Release ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Receptor Activation ◽  
Gabab Receptors ◽  
Inhibitory Synapses ◽  
Receptor Signaling ◽  
Ca1 Region ◽  
Presynaptic Active Zone

AbstractDiverse signaling complexes are precisely assembled at the presynaptic active zone for dynamic modulation of synaptic transmission and synaptic plasticity. Presynaptic GABAB-receptors nucleate critical signaling complexes regulating neurotransmitter release at most synapses. However, the molecular mechanisms underlying assembly of GABAB-receptor signaling complexes remain unclear. Here we show that neurexins are required for the localization and function of presynaptic GABAB-receptor signaling complexes. At four model synapses, excitatory calyx of Held synapses in the brainstem, excitatory and inhibitory synapses on hippocampal CA1-region pyramidal neurons, and inhibitory basket cell synapses in the cerebellum, deletion of neurexins rendered neurotransmitter release significantly less sensitive to GABAB-receptor activation. Moreover, deletion of neurexins caused a loss of GABAB-receptors from the presynaptic active zone of the calyx synapse. These findings extend the role of neurexins at the presynaptic active zone to enabling GABAB-receptor signaling, supporting the notion that neurexins function as central organizers of active zone signaling complexes.

scholarly journals Chemical systems biology reveals mechanisms of glucocorticoid receptor signaling

2021 ◽  
Vol 17 (3) ◽  
pp. 307-316
Author(s):  
Nelson E. Bruno ◽  
Jerome C. Nwachukwu ◽  
Sathish Srinivasan ◽  
Charles C. Nettles ◽  
Tina Izard ◽  
...  
Keyword(s):  
Systems Biology ◽  
Glucocorticoid Receptor ◽  
Receptor Signaling ◽  
Chemical Systems

scholarly journals Revising Endosomal Trafficking under Insulin Receptor Activation

2021 ◽  
Vol 22 (13) ◽  
pp. 6978
Author(s):  
Maria J. Iraburu ◽  
Tommy Garner ◽  
Cristina Montiel-Duarte
Keyword(s):  
Plasma Membrane ◽  
Tyrosine Kinase ◽  
Insulin Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Small Gtpases ◽  
Early Endosome ◽  
Tyrosine Kinase Receptors ◽  
Endosomal Trafficking ◽  
Cell Functions

The endocytosis of ligand-bound receptors and their eventual recycling to the plasma membrane (PM) are processes that have an influence on signalling activity and therefore on many cell functions, including migration and proliferation. Like other tyrosine kinase receptors (TKR), the insulin receptor (INSR) has been shown to be endocytosed by clathrin-dependent and -independent mechanisms. Once at the early endosome (EE), the sorting of the receptor, either to the late endosome (LE) for degradation or back to the PM through slow or fast recycling pathways, will determine the intensity and duration of insulin effects. Both the endocytic and the endosomic pathways are regulated by many proteins, the Arf and Rab families of small GTPases being some of the most relevant. Here, we argue for a specific role for the slow recycling route, whilst we review the main molecular mechanisms involved in INSR endocytosis, sorting and recycling, as well as their possible role in cell functions.

scholarly journals Identification of anticancer drug target genes using an outside competitive dynamics model on cancer signaling networks

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tien-Dzung Tran ◽  
Duc-Tinh Pham
Keyword(s):  
Anticancer Drug ◽  
Drug Target ◽  
Target Genes ◽  
Signaling Network ◽  
Competitive Dynamics ◽  
Signaling Networks ◽  
Molecular Signaling ◽  
Dynamics Model ◽  
Cancer Signaling ◽  
The Impact

AbstractEach cancer type has its own molecular signaling network. Analyzing the dynamics of molecular signaling networks can provide useful information for identifying drug target genes. In the present study, we consider an on-network dynamics model—the outside competitive dynamics model—wherein an inside leader and an opponent competitor outside the system have fixed and different states, and each normal agent adjusts its state according to a distributed consensus protocol. If any normal agent links to the external competitor, the state of each normal agent will converge to a stable value, indicating support to the leader against the impact of the competitor. We determined the total support of normal agents to each leader in various networks and observed that the total support correlates with hierarchical closeness, which identifies biomarker genes in a cancer signaling network. Of note, by experimenting on 17 cancer signaling networks from the KEGG database, we observed that 82% of the genes among the top 3 agents with the highest total support are anticancer drug target genes. This result outperforms those of four previous prediction methods of common cancer drug targets. Our study indicates that driver agents with high support from the other agents against the impact of the external opponent agent are most likely to be anticancer drug target genes.

Transient Removal of Extracellular Mg2+ Elicits Persistent Suppression of LTP at Hippocampal CA1 Synapses Via PKC Activation

2000 ◽  
Vol 84 (3) ◽  
pp. 1279-1288 ◽  
Author(s):  
Kuei-Sen Hsu ◽  
Wen-Chia Ho ◽  
Chiung-Chun Huang ◽  
Jing-Jane Tsai
Keyword(s):  
Nmda Receptor ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Suppressive Effect ◽  
Dependent Protein Kinase ◽  
Dependent Protein

Previous work has shown that seizure-like activity can disrupt the induction of long-term potentiation (LTP). However, how seizure-like event disrupts the LTP induction remains unknown. To understand the cellular and molecular mechanisms underlying this process better, a set of studies was implemented in area CA1 of rat hippocampal slices using extracellular recording methods. We showed here that prior transient seizure-like activity generated by perfused slices with Mg2+-free artificial cerebrospinal fluid (ACSF) exhibited a persistent suppression of LTP induction. This effect lasted between 2 and 3 h after normal ACSF replacement and was specifically inhibited by N-methyl-d-aspartate (NMDA) receptor antagonistd-2-amino-5-phosphovaleric acid (d-APV) and L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). In addition, this suppressive effect was specifically blocked by the selective protein kinase C (PKC) inhibitor NPC-15437. However, neither Ca2+/calmodulin-dependent protein kinase II inhibitor KN-62 nor cAMP-dependent protein kinase inhibitor Rp-adenosine 3′,5′-cyclic monophosphothioate (Rp-cAMPS) affected this suppressive effect. This persistent suppression of LTP was not secondary to the long-lasting changes in NMDA receptor activation, because the isolated NMDA receptor–mediated responses did not show a long-term enhancement in response to a 30-min Mg2+-free ACSF application. Additionally, in prior Mg2+-free ACSF–treated slices, the entire frequency-response curve of LTP and long-term depression (LTD) is shifted systematically to favor LTD. These results suggest that the increase of Ca2+ influx through NMDA channels and L-type VOCCs in turn triggering a PKC-dependent signaling cascade is a possible cellular basis underlying this seizure-like activity-induced inhibition of LTP.

scholarly journals Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Yamaguchi ◽  
Toshihiko Maruyama ◽  
Yoshihiro Urade ◽  
Shigekazu Nagata
Keyword(s):  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Adenosine Monophosphate ◽  
Receptor Activation ◽  
Death Process ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
A2a Adenosine Receptor ◽  
Anti Inflammatory

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal.

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