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American Journal of Physiology. Cell... Jul 2023Proteinase-activated receptors (PARs) are G protein-coupled receptors (GPCRs) activated by limited n-terminal proteolysis. PARs are highly expressed in many cancer...
Proteinase-activated receptors (PARs) are G protein-coupled receptors (GPCRs) activated by limited n-terminal proteolysis. PARs are highly expressed in many cancer cells, including prostate cancer (PCa), and regulate various aspects of tumor growth and metastasis. Specific activators of PARs in different physiological and pathophysiological contexts remain poorly defined. In this study, we examined the androgen-independent human prostatic cancer cell line PC3 and find the functional expression of PAR1 and PAR2, but not PAR4. Using genetically encoded PAR cleavage biosensors, we showed that PC3 cells secrete proteolytic enzymes that cleave PARs and trigger autocrine signaling. CRISPR/Cas9 targeting of PAR1 and PAR2 combined with microarray analysis revealed genes that are regulated through this autocrine signaling mechanism. We found several genes that are known PCa prognostic factors or biomarker to be differentially expressed in the PAR1-knockout (KO) and PAR2-KO PC3 cells. We further examined PAR1 and PAR2 regulation of PCa cell proliferation and migration and found that absence of PAR1 promotes PC3 cell migration and suppresses cell proliferation, whereas PAR2 deficiency showed opposite effects. Overall, these results demonstrate that autocrine signaling through PARs is an important regulator of PCa cell function.
Topics: Male; Humans; Receptor, PAR-1; PC-3 Cells; Autocrine Communication; Receptor, PAR-2; Prostatic Neoplasms
PubMed: 37273236
DOI: 10.1152/ajpcell.00382.2022 -
Molecular and Cellular Endocrinology Jan 2020Follicle-stimulating hormone (FSH) is a glycoprotein hormone produced by gonadotropes in the anterior pituitary that plays a central role in controlling ovarian... (Review)
Review
Follicle-stimulating hormone (FSH) is a glycoprotein hormone produced by gonadotropes in the anterior pituitary that plays a central role in controlling ovarian folliculogenesis and steroidogenesis in females. Moreover, recent studies strongly suggest that FSH exerts extragonadal actions, particularly regulating bone mass and adiposity. Despite its crucial role, the mechanisms regulating FSH secretion are not completely understood. It is evident that hypothalamic, ovarian, and pituitary factors are involved in the neuroendocrine, paracrine, and autocrine regulation of FSH production. Large animal models, such as the female sheep, represent valuable research models to investigate specific aspects of FSH secretory processes. This review: (i) summarizes the role of FSH controlling reproduction and other biological processes; (ii) discusses the hypothalamic, gonadal, and pituitary regulation of FSH secretion; (iii) considers the biological relevance of the different FSH isoforms; and (iv) summarizes the distinct patterns of FSH secretion under different physiological conditions.
Topics: Animals; Autocrine Communication; Female; Follicle Stimulating Hormone; Humans; Hypothalamus; Ovary; Paracrine Communication; Pituitary Gland; Reproduction
PubMed: 31682864
DOI: 10.1016/j.mce.2019.110632 -
General and Comparative Endocrinology Sep 2015Growth hormone (GH) and prolactin (PRL) are both endocrines that are synthesized and released from the pituitary gland into systemic circulation. Both are therefore... (Review)
Review
Growth hormone (GH) and prolactin (PRL) are both endocrines that are synthesized and released from the pituitary gland into systemic circulation. Both are therefore hormones and both have numerous physiological roles mediated through a myriad of target sites and both have pathophysiological consequences when present in excess or deficiency. GH or PRL gene expression is not, however, confined to the anterior pituitary gland and it occurs widely in many of their central and peripheral sites of action. This may reflect "leaky gene" phenomena and the fact that all cells have the potential to express every gene that is present in their genome. However, the presence of GH or PRL receptors in these extrapituitary sites of GH and PRL production suggests that they are autocrine or paracrine sites of GH and PRL action. These local actions often occur prior to the ontogeny of pituitary somatotrophs and lactotrophs and they may complement or differ from the roles of their pituitary counterparts. Many of these local actions are also of physiological significance, since they are impaired by a blockade of local GH or PRL production or by an antagonism of local GH or PRL action. These local actions may also be of pathophysiological significance, since autocrine or paracrine actions of GH and PRL are thought to be causally involved in a number of disease states, particularly in cancer. Autocrine GH for instance, is thought to be more oncogenic than pituitary GH and selective targeting of the autocrine moiety may provide a therapeutic approach to prevent tumor progression. In summary, GH and PRL are not just endocrine hormones, as they have autocrine and/or paracrine roles in health and disease.
Topics: Autocrine Communication; Gene Expression; Human Growth Hormone; Humans; Paracrine Communication; Pituitary Gland; Prolactin
PubMed: 25448258
DOI: 10.1016/j.ygcen.2014.11.004 -
Nature Jun 2022T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs,...
T cell development in the thymus is essential for cellular immunity and depends on the organotypic thymic epithelial microenvironment. In comparison with other organs, the size and cellular composition of the thymus are unusually dynamic, as exemplified by rapid growth and high T cell output during early stages of development, followed by a gradual loss of functional thymic epithelial cells and diminished naive T cell production with age. Single-cell RNA sequencing (scRNA-seq) has uncovered an unexpected heterogeneity of cell types in the thymic epithelium of young and aged adult mice; however, the identities and developmental dynamics of putative pre- and postnatal epithelial progenitors have remained unresolved. Here we combine scRNA-seq and a new CRISPR-Cas9-based cellular barcoding system in mice to determine qualitative and quantitative changes in the thymic epithelium over time. This dual approach enabled us to identify two principal progenitor populations: an early bipotent progenitor type biased towards cortical epithelium and a postnatal bipotent progenitor population biased towards medullary epithelium. We further demonstrate that continuous autocrine provision of Fgf7 leads to sustained expansion of thymic microenvironments without exhausting the epithelial progenitor pools, suggesting a strategy to modulate the extent of thymopoietic activity.
Topics: Aging; Animals; Autocrine Communication; CRISPR-Cas Systems; Cellular Microenvironment; Epithelial Cells; Epithelium; Fibroblast Growth Factor 7; Mice; RNA-Seq; Single-Cell Analysis; Stem Cells; T-Lymphocytes; Thymus Gland
PubMed: 35614226
DOI: 10.1038/s41586-022-04752-8 -
Purinergic Signalling Sep 2021Cancer comprises a collection of diseases that occur in almost any tissue and it is characterized by an abnormal and uncontrolled cell growth that results in tumor... (Review)
Review
Cancer comprises a collection of diseases that occur in almost any tissue and it is characterized by an abnormal and uncontrolled cell growth that results in tumor formation and propagation to other tissues, causing tissue and organ malfunction and death. Despite the undeniable improvement in cancer diagnostics and therapy, there is an urgent need for new therapeutic and preventive strategies with improved efficacy and fewer side effects. In this context, purinergic signaling emerges as an interesting candidate as a cancer biomarker or therapeutic target. There is abundant evidence that tumor cells have significant changes in the expression of purinergic receptors, which comprise the G-protein coupled P2Y and AdoR families of receptors and the ligand-gated ion channel P2X receptors. Tumor cells also exhibit changes in the expression of nucleotidases and other enzymes involved in nucleotide metabolism, and the concentrations of extracellular nucleotides are significantly higher than those observed in normal cells. In this review, we will focus on the potential role of purinergic signaling in the ten most lethal cancers (lung, breast, colorectal, liver, stomach, prostate, cervical, esophagus, pancreas, and ovary), which together are responsible for more than 5 million annual deaths.
Topics: Adenosine Triphosphate; Animals; Autocrine Communication; Humans; Neoplasms; Paracrine Communication; Receptors, Purinergic; Signal Transduction
PubMed: 33982134
DOI: 10.1007/s11302-021-09785-8 -
Stem Cell Research & Therapy Oct 2023Liver fibrosis is prevalent among chronic diseases of the liver and represents a major health burden worldwide. Growth differentiation factor 7 (GDF7), a member of the...
BACKGROUND AND AIM
Liver fibrosis is prevalent among chronic diseases of the liver and represents a major health burden worldwide. Growth differentiation factor 7 (GDF7), a member of the TGFβ protein superfamily, has been recently investigated for its role in repair of injured organs, but its role in chronic liver diseases remains unclear. Here, we examined hepatic GDF7 expression and its association with development and progression of human liver fibrosis. Moreover, we determined the source and target cells of GDF7 in the human liver.
METHODS
GDF7 expression was analyzed in fibrotic and healthy human liver tissues by immunohistochemistry and qPCR. Cell-specific accumulation of GDF7 was examined by immunofluorescence through co-staining of cell type-specific markers on formalin-fixed paraffin-embedded human liver tissues. Public single cell RNA sequence databases were analyzed for cell type-specific expression of GDF7. In vitro, human liver organoids and LX-2 hepatic stellate cells (LX-2) were treated with recombinant human GDF7. Human liver organoids were co-cultured with activated LX-2 cells to induce an autocrine signaling circuit of GDF7 in liver organoids.
RESULTS
GDF7 protein levels were elevated in fibrotic liver tissue, mainly detected in hepatocytes and cholangiocytes. In line, GDF7 mRNA was mainly detected in liver parenchymal cells. Expressions of BMPR1A and BMPR2, encoding GDF7 receptors, were readily detected in hepatocytes, cholangiocytes and stellate cells in vivo and in vitro. In vitro, recombinant GDF7 promoted liver organoid growth and enhanced expression of the progenitor cell markers (LGR5, AXIN2), but failed to activate LX-2 cells. Still, activated LX-2 cells induced GDF7 and LGR5 expression in co-cultured human liver organoids.
CONCLUSIONS
Collectively, this study reveals a role of GDF7 in liver fibrosis and suggests a potential pro-regenerative function that can be utilized for amelioration of hepatic fibrosis caused by chronic liver disease.
Topics: Humans; Autocrine Communication; Hepatic Stellate Cells; Liver; Liver Cirrhosis; Liver Diseases; Stem Cells; Transforming Growth Factor beta1
PubMed: 37798809
DOI: 10.1186/s13287-023-03493-3 -
Trends in Endocrinology and Metabolism:... May 2018The central role of luteinizing hormone (LH) and its receptor (LHCGR) in triggering ovulation has been recognized for decades. Because the LHCGR is present in the mural... (Review)
Review
The central role of luteinizing hormone (LH) and its receptor (LHCGR) in triggering ovulation has been recognized for decades. Because the LHCGR is present in the mural (outermost) granulosa cell layer of preovulatory follicles (POFs), the LH-initiated signal has to be transmitted to another somatic cell type (cumulus granulosa cells) and the oocyte to release a fertilizable oocyte. Recent studies have shown that activation of the LHCGR initiates vectorial transfer of information among the two somatic cell types and the oocyte and the molecules and signaling pathways involved are now better understood. This review summarizes the newer developments on the complex signaling pathways that regulate ovulation.
Topics: Animals; Autocrine Communication; ErbB Receptors; Female; Humans; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Ovulation; Paracrine Communication; Receptors, LH
PubMed: 29602523
DOI: 10.1016/j.tem.2018.02.012 -
Cell Reports Jun 2021The contribution of adipose-derived FGF21 to energy homeostasis is unclear. Here we show that browning of inguinal white adipose tissue (iWAT) by β-adrenergic agonists...
The contribution of adipose-derived FGF21 to energy homeostasis is unclear. Here we show that browning of inguinal white adipose tissue (iWAT) by β-adrenergic agonists requires autocrine FGF21 signaling. Adipose-specific deletion of the FGF21 co-receptor β-Klotho renders mice unresponsive to β-adrenergic stimulation. In contrast, mice with liver-specific ablation of FGF21, which eliminates circulating FGF21, remain sensitive to β-adrenergic browning of iWAT. Concordantly, transgenic overexpression of FGF21 in adipocytes promotes browning in a β-Klotho-dependent manner without increasing circulating FGF21. Mechanistically, we show that β-adrenergic stimulation of thermogenic gene expression requires FGF21 in adipocytes to promote phosphorylation of phospholipase C-γ and mobilization of intracellular calcium. Moreover, we find that the β-adrenergic-dependent increase in circulating FGF21 occurs through an indirect mechanism in which fatty acids released by adipocyte lipolysis subsequently activate hepatic PPARα to increase FGF21 expression. These studies identify FGF21 as a cell-autonomous autocrine regulator of adipose tissue function.
Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic beta-Agonists; Animals; Autocrine Communication; Fibroblast Growth Factors; Gene Expression Regulation; Lipolysis; Liver; Mice; Organ Specificity; Protein Binding; RNA, Messenger; Receptors, Adrenergic, beta-3; Receptors, Fibroblast Growth Factor; Thermogenesis
PubMed: 34192547
DOI: 10.1016/j.celrep.2021.109331 -
Critical Reviews in Immunology 2015Lipocalin-2 (LCN2), a secretory protein, regulates diverse cellular processes such as cell death/survival, cell migration/invasion, cell differentiation, iron delivery,... (Review)
Review
Lipocalin-2 (LCN2), a secretory protein, regulates diverse cellular processes such as cell death/survival, cell migration/invasion, cell differentiation, iron delivery, inflammation, insulin resistance, and tissue regeneration. Recently, we reported that LCN2 is secreted by brain astrocytes under inflammatory conditions and that it promotes apoptosis, morphological changes, and migration in astrocytes both in vitro and in vivo. Activated astrocytes release LCN2 not only to induce the morphological transformation associated with reactive astrocytosis, but also to promote their own death. Under inflammatory conditions, activated astrocytes also show functional dichotomy similar to the M1/M2 phenotypes of microglia and macrophages. LCN2 is thought to be a chemokine inducer and an autocrine promoter of the classical proinflammatory activation of astrocytes. This article summarizes the current knowledge regarding the role of astrocyte-derived LCN2 as a proinflammatory mediator in the central nervous system and discusses LCN2’s role in neuroinflammatory disorders.
Topics: Acute-Phase Proteins; Animals; Apoptosis; Astrocytes; Autocrine Communication; Brain; Humans; Lipocalin-2; Lipocalins; Neurodegenerative Diseases; Neurogenic Inflammation; Proto-Oncogene Proteins
PubMed: 26111426
DOI: 10.1615/critrevimmunol.2015012127 -
Journal of Dairy Science Jan 2016The mammary gland has a remarkable capacity for regulation at a local level, particularly with respect to its main function: milk secretion. Regulation of milk synthesis... (Review)
Review
The mammary gland has a remarkable capacity for regulation at a local level, particularly with respect to its main function: milk secretion. Regulation of milk synthesis has significant effects on animal and human health, at the level of both the mother and the neonate. Control by the mammary gland of its essential function, milk synthesis, is an evolutionary necessity and is therefore tightly regulated at a local level. For at least the last 60 yr, researchers have been interested in elucidating the mechanisms underpinning the mammary gland's ability to self-regulate, largely without the influence from systemic hormones or signals. By the 1960s, scientists realized the importance of milk removal in the capacity of the gland to produce milk and that the dynamics of this removal, including emptying of the alveolar spaces and frequency of milking, were controlled locally as opposed to traditional systemic hormonal regulation. Using both in vitro systems and various mammalian species, including goats, marsupials, humans, and dairy cows, it has been demonstrated that the mammary gland is largely self-regulating in its capacity to support the young, which is the evolutionary basis for milk production. Local control occurs at the level of the mammary epithelial cell through pressure and stretching negative-feedback mechanisms, and also in an autocrine fashion through bioactive factors within the milk which act as inhibitors, regulating milk secretion within the alveoli themselves. It is only within the last 20 to 30 yr that potential candidates for these bioactive factors have been examined at a molecular level. Several, including parathyroid hormone-related protein, growth factors (transforming growth factor, insulin-like growth factor, epidermal growth factor), and serotonin, are synthesized within and act upon the gland and possess dynamic receptor activity resulting in diverse effects on growth, calcium homeostasis, and milk composition. This review will focus on the autocrine-paracrine regulation of the mammary gland, with an examination of both foundational work and the progress made within the last 10 to 20 yr of research.
Topics: Animals; Autocrine Communication; Cattle; Epithelial Cells; Female; Goats; Humans; Lactation; Mammary Glands, Animal; Mammary Glands, Human; Milk; Paracrine Communication; Parathyroid Hormone-Related Protein; Prolactin; Serotonin
PubMed: 26299162
DOI: 10.3168/jds.2015-9828