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Cell Communication and Signaling : CCS Apr 2023The secreted protein augurin, the product of the tumor suppressor gene Ecrg4, has been identified as a peptide hormone in the human proteome in 2007. Since then, a... (Review)
Review
The secreted protein augurin, the product of the tumor suppressor gene Ecrg4, has been identified as a peptide hormone in the human proteome in 2007. Since then, a number of studies have been carried out to highlight its structure and processing and its potential roles in physiopathology. Although augurin has been shown to be implicated in a variety of processes, ranging from tumorigenesis, inflammation and infection to neural stem cell proliferation, hypothalamo-pituitary adrenal axis regulation and osteoblast differentiation, the molecular mechanisms of its biological effects and the signaling pathways it regulates are still poorly characterized. Here we provide a comprehensive overview of augurin-dependent signal transduction pathways. Because of their secreted nature and the potential to be manipulated pharmacologically, augurin and its derived peptides represent attractive targets for diagnostic development and discovery of new therapeutic agents for the human diseases resulting from the deregulation of the signaling cascades they modulate. From this perspective, the characterization of the precise nature of augurin derived peptides and the identification of the receptor(s) on the cell surface conveying augurin signaling to downstream effectors are crucial to develop agonists and antagonists for this protein. Video abstract.
Topics: Humans; Tumor Suppressor Proteins; Peptide Hormones; Proteome; Signal Transduction
PubMed: 37041625
DOI: 10.1186/s12964-023-01090-8 -
Nature Communications Mar 2024Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the...
Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.
Topics: Animals; Female; Humans; Mice; Endometriosis; Endometrium; Estrogens; Neoplasm Proteins; Progesterone; Receptors, Progesterone; Receptors, Steroid; Steroids
PubMed: 38431630
DOI: 10.1038/s41467-024-46180-4 -
European Journal of Medicinal Chemistry Sep 2019Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a... (Review)
Review
Breast cancer, a most common malignancy in women, was known to be associated with steroid hormone estrogen. The discovery of estrogen receptor (ER) gave us not only a powerful predictive and prognostic marker, but also an efficient target for the treatment of hormone-dependent breast cancer with various estrogen ligands. ER consists of two subtypes i.e. ERα and ERβ, that are mostly G-protein-coupled receptors and activated by estrogen, specially 17β-estradiol. The activation is followed by translocation into the nucleus and binding with DNA to modulate activities of different genes. ERs can manage synthesis of RNA through genomic actions without directly binding to DNA. Receptors are tethered by protein-protein interactions to a transcription factor complex to communicate with DNA. Estrogens also exhibit nongenomic actions, a characteristic feature of steroid hormones, which are so rapid to be considered by the activation of RNA and translation. These are habitually related to stimulation of different protein kinase cascades. Majority of post-menopausal breast cancer is estrogen dependent, mostly potent biological estrogen (E2) for continuous growth and proliferation. Estrogen helps in regulating the differentiation and proliferation of normal breast epithelial cells. In this review we have investigated the important role of ER in development and progression of breast cancer, which is complicated by receptor's interaction with co-regulatory proteins, cross-talk with other signal transduction pathways and development of treatment strategies viz. selective estrogen receptor modulators (SERMs), selective estrogen receptor down regulators (SERDs), aromatase and sulphatase inhibitors.
Topics: Aromatase Inhibitors; Breast Neoplasms; Cell Line, Tumor; Estrogen Antagonists; Estrogens; Female; Humans; Ligands; Men; Molecular Structure; Receptors, Estrogen; Selective Estrogen Receptor Modulators; Signal Transduction; Sulfatases
PubMed: 31129450
DOI: 10.1016/j.ejmech.2019.05.023 -
ELife Jan 2022Cholesterol is a major component of the cell membrane and commonly regulates membrane protein function. Here, we investigate how cholesterol modulates the conformational...
Cholesterol is a major component of the cell membrane and commonly regulates membrane protein function. Here, we investigate how cholesterol modulates the conformational equilibria and signaling of the adenosine A receptor (AR) in reconstituted phospholipid nanodiscs. This model system conveniently excludes possible effects arising from cholesterol-induced phase separation or receptor oligomerization and focuses on the question of allostery. GTP hydrolysis assays show that cholesterol weakly enhances the basal signaling of AR while decreasing the agonist EC. Fluorine nuclear magnetic resonance (F NMR) spectroscopy shows that this enhancement arises from an increase in the receptor's active state population and a G-protein-bound precoupled state. F NMR of fluorinated cholesterol analogs reveals transient interactions with AR, indicating a lack of high-affinity binding or direct allosteric modulation. The combined results suggest that the observed allosteric effects are largely indirect and originate from cholesterol-mediated changes in membrane properties, as shown by membrane fluidity measurements and high-pressure NMR.
Topics: Allosteric Regulation; Animals; Cholesterol; Escherichia coli; Magnetic Resonance Spectroscopy; Receptor, Adenosine A2A; Saccharomycetales; Sf9 Cells; Spodoptera
PubMed: 34986091
DOI: 10.7554/eLife.73901 -
Hormone and Metabolic Research =... Jun 2024Melatonin (5-methoxy-acetyl tryptamine) is a sleep-inducing hormone, and the pineal gland produces it in response to the circadian clock of darkness. In the body, MT1... (Review)
Review
Melatonin (5-methoxy-acetyl tryptamine) is a sleep-inducing hormone, and the pineal gland produces it in response to the circadian clock of darkness. In the body, MT1 and MT2 receptors are mostly found, having an orthosteric pocket and ligand binding determinants. Melatonin acts by binding on melatonin receptors, intracellular proteins, and orphan nuclear receptors. It inhibits adenyl cyclase and activates phospholipase C, resulting in gene expression and an intracellular alteration environment. Melatonin signaling pathways are also associated with other intracellular signaling pathways, i. e., cAMP/PKA and MAPK/ERK pathways. Relative expression of different proteins depends on the coupling profile of G protein, accounting pharmacology of the melatonin receptor bias system, and mediates action in a Gi-dependent manner. It shows antioxidant, antitumor, antiproliferative, and neuroprotective activity. Different types of melatonin agonists have been synthesized for the treatment of sleeping disorders. Researchers have developed therapeutics that target melatonin signaling, which could benefit a wide range of medical conditions. This review focuses on melatonin receptors, pharmacology, and signaling cascades; it aims to provide basic mechanical aspects of the receptor's pharmacology, melatonin's functions in cancer and neurodegenerative diseases, and any treatments and drugs designed for these diseases. This will allow a basic comparison between the receptors in question, highlighting any parallels and differences that may exist and providing fundamental knowledge about these receptors to future researchers.
Topics: Humans; Melatonin; Signal Transduction; Animals; Receptors, Melatonin; Neoplasms; Neurodegenerative Diseases
PubMed: 38081221
DOI: 10.1055/a-2226-3971 -
Cells Jun 2022The nuclear progesterone receptor (PR) is mainly known for its role as a ligand-regulated transcription factor. However, in the last ten years, this receptor's... (Review)
Review
The nuclear progesterone receptor (PR) is mainly known for its role as a ligand-regulated transcription factor. However, in the last ten years, this receptor's extranuclear or rapid actions have gained importance in the context of physiological and pathophysiological conditions such as cancer. The PR's polyproline (PXPP) motif allows protein-protein interaction through SH3 domains of several cytoplasmatic proteins, including the Src family kinases (SFKs). Among members of this family, cSrc is the most well-characterized protein in the scenario of rapid actions of the PR in cancer. Studies in breast cancer have provided the most detailed information on the signaling and effects triggered by the cSrc-PR interaction. Nevertheless, the study of this phenomenon and its consequences has been underestimated in other types of malignancies, especially those not associated with the reproductive system, such as glioblastomas (GBs). This review will provide a detailed analysis of the impact of the PR-cSrc interplay in the progression of some non-reproductive cancers, particularly, in GBs.
Topics: Breast Neoplasms; Female; Humans; Progesterone; Protein-Tyrosine Kinases; Receptors, Progesterone; src-Family Kinases
PubMed: 35741094
DOI: 10.3390/cells11121964 -
Combinatorial Chemistry & High... 2021
Topics: Antiviral Agents; Drug Design; Humans; Molecular Dynamics Simulation; Molecular Structure
PubMed: 34259135
DOI: 10.2174/138620732407210504100334 -
Cell Surface (Amsterdam, Netherlands) Dec 2023
Review
PubMed: 37396714
DOI: 10.1016/j.tcsw.2023.100100 -
Current Medicinal Chemistry Aug 2023Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and...
BACKGROUND
Numerous biochemical reactions leading to altered cell proliferation cause tumorigenesis and cancer treatment resistance. The mechanisms implicated include genetic and epigenetic changes, modified intracellular signaling, and failure of control mechanisms caused by intrinsic and extrinsic factors alone or combined. No unique biochemical events are responsible; entangled molecular reactions conduct the resident cells in a tissue to display uncontrolled growth and abnormal migration. Copious experimental research supports the etiological responsibility of NK-1R (neurokinin-1 receptor) activation, alone or cooperating with other mechanisms, in cancer appearance in different tissues. Consequently, a profound study of this receptor system in the context of malignant processes is essential to design new treatments targeting NK-1R-deviated activity.
METHOD
This study reviews and discusses recent literature that analyzes the main signaling pathways influenced by the activation of neurokinin 1 full and truncated receptor variants. Also, the involvement of NK-1R in cancer development is discussed.
CONCLUSION
NK-1R can signal through numerous pathways and cross-talk with other receptor systems. The participation of override or malfunctioning NK-1R in malignant processes needs a more precise definition in different types of cancers to apply satisfactory and effective treatments. A long way has already been traveled: the current disposal of selective and effective NK-1R antagonists and the capacity to develop new drugs with biased agonistic properties based on the receptor's structural states with functional significance opens immediate research action and clinical application.
PubMed: 37594106
DOI: 10.2174/0929867331666230818110812 -
International Journal of Molecular... Jan 2020Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent... (Review)
Review
Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology have advanced considerably in recent years. A wealth of data show that 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows the rescue of long-term potentiation (LTP) and long-term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, modulates the function of immune cells, and is likely to play a role in the gut-brain axis. In this review, we will mainly focus on recent findings on this receptor's role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gastrointestinal (GI) tract and immune system.
Topics: Animals; Brain; Disease Models, Animal; Humans; Intestinal Diseases; Intestines; Long-Term Potentiation; Long-Term Synaptic Depression; Mental Disorders; Neurodevelopmental Disorders; Receptors, Serotonin
PubMed: 31941109
DOI: 10.3390/ijms21020505