scholarly journals Role of GPER-Mediated Signaling in Testicular Functions and Tumorigenesis

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2115
Author(s):  
Adele Chimento ◽  
Arianna De Luca ◽  
Marta Claudia Nocito ◽  
Paola Avena ◽  
Davide La Padula ◽  
...  
Keyword(s):  
Leydig Cells ◽  
Somatic Cells ◽  
Estrogen Signaling ◽  
Specific Cell ◽  
Cell Type ◽  
Cancer Cell Growth ◽  
Testicular Cells ◽  
G Protein Coupled ◽  
Receptor Family

Estrogen signaling plays important roles in testicular functions and tumorigenesis. Fifteen years ago, it was discovered that a member of the G protein-coupled receptor family, GPR30, which binds also with high affinity to estradiol and is responsible, in part, for the rapid non-genomic actions of estrogens. GPR30, renamed as GPER, was detected in several tissues including germ cells (spermatogonia, spermatocytes, spermatids) and somatic cells (Sertoli and Leydig cells). In our previous review published in 2014, we summarized studies that evidenced a role of GPER signaling in mediating estrogen action during spermatogenesis and testis development. In addition, we evidenced that GPER seems to be involved in modulating estrogen-dependent testicular cancer cell growth; however, the effects on cell survival and proliferation depend on specific cell type. In this review, we update the knowledge obtained in the last years on GPER roles in regulating physiological functions of testicular cells and its involvement in neoplastic transformation of both germ and somatic cells. In particular, we will focus our attention on crosstalk among GPER signaling, classical estrogen receptors and other nuclear receptors involved in testis physiology regulation.

scholarly journals Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors

2021 ◽  
Vol 8 ◽  
Author(s):  
Giuseppe Deganutti ◽  
Silvia Atanasio ◽  
Roxana-Maria Rujan ◽  
Patrick M. Sexton ◽  
Denise Wootten ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Approved Drugs ◽  
G Protein Coupled ◽  
Dynamic Docking ◽  
Receptor Family

Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.

scholarly journals Estrogen receptors and function in the male reproductive system

2009 ◽  
Vol 53 (8) ◽  
pp. 923-933 ◽  
Author(s):  
Maria Fatima Magalhães Lazari ◽  
Thais Fabiana Gameiro Lucas ◽  
Fabiana Yasuhara ◽  
Gisele Renata Oliveira Gomes ◽  
Erica Rosanna Siu ◽  
...  
Keyword(s):  
Growth Factors ◽  
Estrogen Receptors ◽  
Reproductive System ◽  
Male Reproductive System ◽  
Estrogen Signaling ◽  
Nuclear Receptor Family ◽  
And Function ◽  
Rapid Signaling ◽  
G Protein Coupled ◽  
Receptor Family

A substantial advance in our understanding on the estrogen signaling occurred in the last decade. Estrogens interact with two receptors, ESR1 and ESR2, also known as ERα and ERβ, respectively. ESR1 and ESR2 belong to the nuclear receptor family of transcription factors. In addition to the well established transcriptional effects, estrogens can mediate rapid signaling, triggered within seconds or minutes. These rapid effects can be mediated by ESRs or the G protein-coupled estrogen receptor GPER, also known as GPR30. The effects of estrogen on cell proliferation, differentiation and apoptosis are often mediated by growth factors. The understanding of the cross-talk between androgen, estrogen and growth factors signaling pathways is therefore essential to understand the physiopathological mechanisms of estrogen action. In this review we focused on recent discoveries about the nature of the estrogen receptors, and on the signaling and function of estrogen in the male reproductive system.

scholarly journals The Stability of the Induced Epigenetic Programs

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Maria J. Barrero
Keyword(s):  
Stem Cells ◽  
Somatic Cells ◽  
Cell Types ◽  
Specific Cell ◽  
Cell Type ◽  
Pluripotent Cells ◽  
Potential Applications ◽  
The Stability

For many years scientists have been attracted to the possibility of changing cell identity. In the last decades seminal discoveries have shown that it is possible to reprogram somatic cells into pluripotent cells and even to transdifferentiate one cell type into another. In view of the potential applications that generating specific cell types in the laboratory can offer for cell-based therapies, the next important questions relate to the quality of the induced cell types. Importantly, epigenetic aberrations in reprogrammed cells have been correlated with defects in differentiation. Therefore, a look at the epigenome and understanding how different regulators can shape it appear fundamental to anticipate potential therapeutic pitfalls. This paper covers these epigenetic aspects in stem cells, differentiation, and reprogramming and discusses their importance for the safety of in vitro engineered cell types.

scholarly journals Inducing your neighbors to become like you: Cell recruitment and its contribution to developmental patterning and growth

2020 ◽  
Vol 52 ◽  
Author(s):  
Luis Manuel Muñoz-Nava ◽  
Marycruz Flores-Flores ◽  
Marcos Nahmad
Keyword(s):  
Specific Cell ◽  
Cell Type ◽  
Recruitment Process ◽  
Cell Recruitment ◽  
Drosophila Wing ◽  
Differentiated Cells ◽  
Open Questions ◽  
Developmental Patterning ◽  
Type Population

Cell differentiation, proliferation, and morphogenesis are generally driven by instructive signals that are sent and interpreted by adjacent tissues, a process known as induction. Cell recruitment is a particular case of induction in which differentiated cells produce a signal that drives adjacent cells to differentiate into the same type as the inducers. Once recruited, these new cells may become inducers to continue the recruitment process, closing a feed-forward loop that propagates the growth of a specific cell-type population. So far, little attention has been given to cell recruitment as a developmental mechanism. Here, we review the components of cell recruitment and discuss its contribution to development in three different examples: the Drosophila wing, the vertebrate inner ear, and the mammalian thyroid gland. Finally, we posit some open questions about the role of cell recruitment in organ patterning and growth.

scholarly journals Postnatal Lethality in Mice Lacking the Sax2 Homeobox Gene Homologous to Drosophila S59/slouch: Evidence for Positive and Negative Autoregulation

2003 ◽  
Vol 23 (24) ◽  
pp. 9046-9060 ◽  
Author(s):  
Ruth Simon ◽  
Thomas Lufkin
Keyword(s):  
Null Allele ◽  
Homeobox Gene ◽  
Premature Death ◽  
Specific Cell ◽  
Cell Type ◽  
High Similarity ◽  
Cell Specification ◽  
Ventral Neural Tube ◽  
Positive And Negative Feedback

ABSTRACT Homeobox gene transcription factors direct multiple functions during development. They are involved in early patterning of the embryo as well as cell specification, cell differentiation, and organogenesis. Here we describe a previously uncharacterized murine homeobox gene, Sax2, that shows high similarity to the Drosophila S59/slouch and murine Sax1 genes. We show that Sax2 gene expression occurs early during embryogenesis in the midbrain, the midbrain-hindbrain boundary, the ventral neural tube, the developing eye, and the apical ectodermal ridge of the limb. To determine the role of Sax2 during development, we generated a knockout mouse line by replacing part of the Sax2 coding sequences with the lacZ gene. The Sax2 null allele mutants exhibit a strong phenotype indicated by growth retardation starting immediately after birth and leading to premature death within the first 3 weeks postnatal. Intriguingly, our studies also demonstrated a striking autoregulation of the Sax2 gene in both positive- and negative-feedback mechanisms depending on the specific cell type expressing Sax2.

Role of angiogenesis factors in formation of metastatic niches.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15534-e15534
Author(s):  
Elena M. Frantsiyants ◽  
Oleg I. Kit ◽  
Irina V. Kaplieva ◽  
Yuriy A. Gevorkyan ◽  
Natalya V. Soldatkina ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Growth Factors ◽  
Tumor Cells ◽  
Comparison Group ◽  
Metastatic Tumor ◽  
Specific Cell ◽  
Cell Type ◽  
Metastatic Niche ◽  
Mesenchymal Transition

e15534 Background: A metastatic niche indicates a particular location with a specific cell type, epidermal-mesenchymal transition proteins and diffuse signals that are necessary for the growth of metastases. The purpose of the study was to determine levels of VEGFs, their receptors and TGFβ1 in tissues of gastric cancer (GC) and its metastatic niches: the peritoneum and omentum. Methods: The main group included 21 patients with metastatic GC T3-4аN0-3M1; comparison group – 17 non-cancer patients. Levels of VEGFA, VEGFC, sVEGFR1, sVEGFR3 and TGFβ1 in tissues were determined by standard ELISA methods. Results: Levels of growth factors in GC tissues were higher than in controls: VEGFA in T3-4аN0-3M1 – by 2.7 times, in T3-4аN0-3M0 – by 2.5 times; TGFβ1 in T3-4аN0-3M1 – by 5.6 times, in T3-4аN0-3M0 – by 3.5 times. VEGFA levels in primary gastric tumors were similar in all patients, while TGFβ1 in T3-4аN0-3M1 was 1.6 times (p < 0.05) higher than in T3-4аN0-3M0. VEGFA levels in T3-4аN0-3M1 exceeded control values: in the omentum – by 2.8, in the peritoneum – by 4.2 times. TGFβ1 in the omentum and peritoneum in T3-4аN0-3M1 was increased by 2.5 and 3.1 times respectively, compared to controls. Statistically significant differences in VEGFA and TGFβ1 levels in the omentum and peritoneum in T3-4аN0-3M0 were not found. Conclusions: GC is characterized by equally elevated levels of VEGFA, regardless of the presence or absence of metastases. In the omentum and peritoneum with metastases, high VEGF levels can be considered as one of the primary factors for the formation of signaling pathways between metastatic tumor cells and local non-tumor cells in premetastatic niches. Levels of TGFβ1 in the omentum and peritoneum increase only in patients with metastases, and in GC tissue they are increased to a greater extent than in patients without metastases. Probably, in case of T3-4aN0-3M0, the factor produced by the primary tumor was insufficient for its paracrine induction in the metastatic niche, and scattered cells could not transit from “sleeping” to the active state.

scholarly journals Getting the message across: Pathophysiology and signaling via receptors for polypeptide hormones and proteinases

2010 ◽  
Vol 33 (2) ◽  
pp. 133 ◽  
Author(s):  
Morley D Hollenberg
Keyword(s):  
Drug Targets ◽  
Time Span ◽  
Activation Mechanism ◽  
Therapeutic Implications ◽  
Proteinase Activated Receptors ◽  
Tethered Ligand ◽  
Polypeptide Hormones ◽  
G Protein Coupled ◽  
Receptor Family

This article provides a personalized overview of the role of proteinases in generating hormone-like cell signals. Also outlined is the unexpected route of discovery that led one investigator over a four-decade time span, from early studies of the interactions of oxytocin and vasopressin with their neurophysin binding proteins to current studies of the tethered ligand activation mechanism that is unique for the G-protein-coupled family of proteinase-activated receptors (PARs). The focus is not only on the intriguing PAR receptor family, but also on alternative mechanisms whereby proteinases activate signal transduction pathways. Also summarized are the potential physiological and pathophysiological roles that PARs may play in the setting of inflammatory disorders ranging from arthritis to colitis. The therapeutic implications of considering PARs as drug targets are also discussed.

scholarly journals Reorganisation of chromatin during erythroid differentiation

2019 ◽  
Vol 23 (1) ◽  
pp. 95-99
Author(s):  
A. A. Khabarova ◽  
A. S. Ryzhkova ◽  
N. R. Battulin
Keyword(s):  
Chromatin Structure ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Erythroid Differentiation ◽  
Gene Activity ◽  
Nuclear Space ◽  
Specific Cell ◽  
Cell Type ◽  
Differentiation Potential

A totipotent zygote has unlimited potential for differentiation into all cell types found in an adult organism. During ontogenesis proliferating and maturing cells gradually lose their differentiation potential, limiting the spectrum of possible developmental transitions to a specific cell type. Following the initiation of the developmental program cells acquire specific morphological and functional properties. Deciphering the mechanisms that coordinate shifts in gene expression revealed a critical role of three-dimensional chromatin structure in the regulation of gene activity during lineage commitment. Several levels of DNA packaging have been recently identified using chromosome conformation capture based techniques such a Hi-C. It is now clear that chromatin regions with high transcriptional activity assemble into Mb-scale compartments in the nuclear space, distinct from transcriptionally silent regions. More locally chromatin is organized into topological domains, serving as functionally insulated units with cell type – specific regulatory loop interactions. However, molecular mechanisms establishing and maintaining such 3D organization are yet to be investigated. Recent focus on studying chromatin reorganization accompanying cell cycle progression and cellular differentiation partially explained some aspects of 3D genome folding. Throughout erythropoiesis cells undergo a dramatic reorganization of the chromatin landscape leading to global nuclear condensation and transcriptional silencing, followed by nuclear extrusion at the final stage of mammalian erythropoiesis. Drastic changes of genome architecture and function accompanying erythroid differentiation seem to be an informative model for studying the ways of how genome organization and dynamic gene activity are connected. Here we summarize current views on the role of global rearrangement of 3D chromatin structure in erythroid differentiation.

scholarly journals GC-1 spg cells are most similar to Leydig cells, a testis somatic cell-type, and not germ cells

2021 ◽  
Author(s):  
Andrew R Norman ◽  
Lauren Byrnes ◽  
Jeremy R Reiter
Keyword(s):  
Germ Cell ◽  
Somatic Cell ◽  
Cell Line ◽  
Germ Cells ◽  
Leydig Cells ◽  
Adult Mouse ◽  
Somatic Cells ◽  
Cell Type ◽  
Immortalized Cell ◽  
Somatic Cell Type

GC-1 spg is an immortalized cell line derived from an adult mouse testis and reported to be most similar to spermatocytes, a male germ cell-type. However, immunofluorescence indicates that GC-1 spg cells express WT1, a marker of testis somatic cells, and do not express markers of germ cells. Transcriptomic profiling indicate GC-1 cells are most similar to Leydig cells. Therefore, we conclude that GC-1 spg cells are most similar to testis somatic cells.

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