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Canadian Journal of Veterinary Research... Jul 2021The purpose of this study was to analyze the morpho-functional features of the ovaries and uterus of sows with different genotypes for the estrogen receptor , prolactin...
Evaluation of reproductive traits and ovarian and uterine morphology of sows with different genotypes for the estrogen receptor, prolactin receptor, and follicle-stimulating hormone subunit beta genes.
The purpose of this study was to analyze the morpho-functional features of the ovaries and uterus of sows with different genotypes for the estrogen receptor , prolactin receptor , and follicle-stimulating hormone subunit beta β genes associated with reproductive traits. Healthy Large White sows were studied. The genotypic status of the , and β genes was detected by polymerase chain reaction-restriction fragment length polymorphism. The structure of the ovaries and uterus was studied using quantitative assessment of organs and histological research. Sows with the genotype significantly exceeded animals with the genotype in milk yield (by 0.3 kg) and in the number of piglets at birth (by 0.9 animals) and at weaning (by 0.7 animals). Sows with the genotype were midway between those with and genotypes in terms of these reproductive traits. Animals with the genotype significantly exceeded those with the genotype in the number of piglets born ( < 0.05); the differences in litter weight at birth were not significant. Compared to other genotypes, sows with genotypes ( < 0.05) and ( < 0.05) had larger uteruses and more yellow bodies, tertiary follicles, and primordial follicles in their ovaries. Animals with the β genotype significantly exceeded animals with the β genotype in the length of uterus by 21 cm ( < 0.05).
Topics: Animals; Female; Follicle Stimulating Hormone, beta Subunit; Gene Expression Regulation; Ovary; Pregnancy; Receptors, Estrogen; Receptors, Prolactin; Swine; Uterus
PubMed: 34248262
DOI: No ID Found -
Frontiers in Endocrinology 2021Prolactin (PRL) levels are reduced in the circulation of rats with diabetes or obesity, and lower circulating levels of PRL correlate with increased prevalence of...
Prolactin (PRL) levels are reduced in the circulation of rats with diabetes or obesity, and lower circulating levels of PRL correlate with increased prevalence of diabetes and a higher risk of metabolic alterations in the clinic. Furthermore, PRL stimulates β-cell proliferation, survival, and insulin production and pregnant mice lacking PRL receptors in β-cells develop gestational diabetes. To investigate the protective effect of endogenous PRL against diabetes outside pregnancy, we compared the number of cases and severity of streptozotocin (STZ)-induced hyperglycemia between C57BL/6 mice null for the PRL receptor gene ( ) and wild-type mice ( ). STZ-treated diabetic mice showed a higher number of cases and later recovery from hyperglycemia, exacerbated glucose levels, and glucose intolerance compared to the mice counterparts. Consistent with the worsening of hyperglycemia, pancreatic islet density, β-cell number, proliferation, and survival, as well as circulating insulin levels were reduced, whereas α-cell number and pancreatic inflammation were increased in the absence of PRL signaling. Deletion of the PRL receptor did not alter the metabolic parameters in vehicle-treated animals. We conclude that PRL protects whole body glucose homeostasis by reducing β-cell loss and pancreatic inflammation in STZ-induced diabetes. Medications elevating PRL circulating levels may prove to be beneficial in diabetes.
Topics: Animals; Blood Glucose; Cell Proliferation; Cell Survival; Diabetes Mellitus, Experimental; Glucose Intolerance; Insulin; Insulin-Secreting Cells; Mice; Receptors, Prolactin
PubMed: 33746901
DOI: 10.3389/fendo.2021.619696 -
The American Journal of Pathology Mar 1999In situ hybridization and immunohistochemistry were used to localize and compare the expression of the long form of the human prolactin receptor in fetal, prepubertal,...
In situ hybridization and immunohistochemistry were used to localize and compare the expression of the long form of the human prolactin receptor in fetal, prepubertal, and adult prostate. Results were then compared with hyperplastic, dysplastic, and neoplastic lesions. Both receptor message and protein were predominately localized in epithelial cells of the fetal, neonatal, prepubertal, and normal adult prostate. In hyperplastic lesions the expression of the receptor was unchanged with respect to normal epithelial cells. Irrespective of grade, markedly enhanced expression of the receptor was evident in dysplastic lesions. In lower Gleason grade carcinomas the intensity of receptor signal at the message and protein levels approximated that found in normal prostatic epithelium. However, in foci within higher grade cancers, receptor expression appeared diminished. Results from our study suggest that prolactin action plays a role in the development and maintenance of the human prostate and may also participate in early neoplastic transformation of the gland. Diminution of receptor expression in high grade neoplasms could reflect the emergence of a population of cells that are no longer responsive to the peptide hormone.
Topics: Aged; Aging; Carcinoma; Embryonic and Fetal Development; Fetus; Humans; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Puberty; Receptors, Prolactin; Reference Values
PubMed: 10079264
DOI: 10.1016/S0002-9440(10)65333-3 -
Neuroendocrinology 2013The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated... (Review)
Review
The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated in this regulation and lately, prolactin (PRL) has been included into that list. However, since PRL is secreted by anterior pituitary lactotropes, the actual outcome of its autocrine/paracrine actions on pituitary cells has remained difficult to assess. The availability of the pure PRL receptor antagonist Del1-9-G129R-hPRL has been helpful to circumvent this problem. While PRL has been traditionally associated with increased cell proliferation, recent studies revealed that this hormone actually induces apoptosis and decreases proliferation of anterior pituitary cells, by mechanisms involving the PRL receptor. The aim of this short review is to overview our current understanding of the regulation of pituitary homeostasis by PRL. Moreover, studies involving Del1-9-G129R-hPRL have helped anticipate to what extent future treatments involving PRL receptor inhibitors may interfere with processes regulated by PRL at the central level.
Topics: Animals; Homeostasis; Humans; Pituitary Gland; Prolactin; Protein Binding; Receptors, Prolactin; Signal Transduction
PubMed: 23969780
DOI: 10.1159/000354701 -
Poultry Science May 2011Prolactin receptor (PRLR) is a single transmembrane protein through which prolactin plays a wide variety of physiological roles in vertebrates. To understand its role in...
Prolactin receptor (PRLR) is a single transmembrane protein through which prolactin plays a wide variety of physiological roles in vertebrates. To understand its role in goose behavior, we cloned the gene of goose PRLR (gPRLR) in the Siji goose, a domestic goose with strong broodiness in China, and examined its expression level in different organs of adult geese. Our results showed that gPRLR cDNA contained 443 bp 5' untranslated region, 2,496 bp coding sequence that presumably comprises at least 14 exons, and 220 bp 3' untranslated region. The predicted goose PRLR contained 831 amino acids and exhibited identities of 87.7, 85.2, and 84.8% with chicken, pigeon, and turkey PRLR, respectively. It comprised a signal peptide of 24 amino acids at the N terminus, 2 ligand binding regions of the extracellular domain, each containing 2 pairs of cysteine residues and a pentapeptide of 5 amino acids known as WS motif (Tpr-Ser-any amino acid-Tpr-Ser), the 2 typical features highly conserved in the members of class 1 cytokine receptor superfamily. Phylogenetic analysis revealed that the goose PRLR is highly conserved during evolution. In addition, we discovered 2 other alternative splicing transcripts of gPRLR. One is generated by missing the last 95 bp of the first 330 bp of the 3,159 bp cDNA. The other is produced by an alternative transcription initiation, leading to creation of a novel first exon that is directly spliced to the third exon. Reverse transcription PCR analyses show that the gPRLR mRNA is widely expressed in the testis, seminal duct, ovary, oviduct, kidney, large intestine, and small intestine.
Topics: Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; Geese; Gene Expression Regulation; Molecular Sequence Data; Phylogeny; Protein Isoforms; Receptors, Prolactin; Reverse Transcriptase Polymerase Chain Reaction; Species Specificity
PubMed: 21489954
DOI: 10.3382/ps.2010-01300 -
The New England Journal of Medicine Nov 2013Hyperprolactinemia that is not associated with gestation or the puerperium is usually due to tumors in the anterior pituitary gland and occurs occasionally in hereditary...
Hyperprolactinemia that is not associated with gestation or the puerperium is usually due to tumors in the anterior pituitary gland and occurs occasionally in hereditary multiple endocrine neoplasia syndromes. Here, we report data from three sisters with hyperprolactinemia, two of whom presented with oligomenorrhea and one with infertility. These symptoms were not associated with pituitary tumors or multiple endocrine neoplasia but were due to a heterozygous mutation in the prolactin receptor gene, PRLR, resulting in an amino acid change from histidine to arginine at codon 188 (His188Arg). This substitution disrupted the high-affinity ligand-binding interface of the prolactin receptor, resulting in a loss of downstream signaling by Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Thus, the familial hyperprolactinemia appears to be due to a germline, loss-of-function mutation in PRLR, resulting in prolactin insensitivity.
Topics: Adult; Female; Germ-Line Mutation; Humans; Hyperprolactinemia; Janus Kinase 2; Male; Pedigree; Protein Conformation; Receptors, Prolactin; STAT5 Transcription Factor; Sequence Analysis, DNA; Signal Transduction
PubMed: 24195502
DOI: 10.1056/NEJMoa1307557 -
American Journal of Physiology.... Feb 2012Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could exert autocrine or paracrine actions on anterior pituitary cells. In...
Since anterior pituitary expresses prolactin receptors, prolactin secreted by lactotropes could exert autocrine or paracrine actions on anterior pituitary cells. In fact, it has been observed that prolactin inhibits its own expression by lactotropes. Our hypothesis is that prolactin participates in the control of anterior pituitary cell turnover. In the present study, we explored the action of prolactin on proliferation and apoptosis of anterior pituitary cells and its effect on the expression of the prolactin receptor. To determine the activity of endogenous prolactin, we evaluated the effect of the competitive prolactin receptor antagonist Δ1-9-G129R-hPRL in vivo, using transgenic mice that constitutively and systemically express this antagonist. The weight of the pituitary gland and the anterior pituitary proliferation index, determined by BrdU incorporation, were higher in transgenic mice expressing the antagonist than in wild-type littermates. In addition, blockade of prolactin receptor in vitro by Δ1-9-G129R-hPRL increased proliferation and inhibited apoptosis of somatolactotrope GH3 cells and of primary cultures of male rat anterior pituitary cells, including lactotropes. These results suggest that prolactin acts as an autocrine/paracrine antiproliferative and proapoptotic factor in the anterior pituitary gland. In addition, anterior pituitary expression of the long isoform of the prolactin receptor, measured by real-time PCR, increased about 10-fold in transgenic mice expressing the prolactin receptor antagonist, whereas only a modest increase in the S3 short-isoform expression was observed. These results suggest that endogenous prolactin may regulate its own biological actions in the anterior pituitary by inhibiting the expression of the long isoform of the prolactin receptor. In conclusion, our observations suggest that prolactin is involved in the maintenance of physiological cell renewal in the anterior pituitary. Alterations in this physiological role of prolactin could contribute to pituitary tumor development.
Topics: Animals; Apoptosis; Cell Line; Cell Proliferation; Cells, Cultured; Gene Expression Regulation; Hormone Antagonists; Male; Mice; Mice, Inbred BALB C; Mice, Transgenic; Organ Size; Pituitary Gland, Anterior; Prolactin; Protein Isoforms; RNA, Messenger; Rats; Rats, Wistar; Receptors, Prolactin; Recombinant Proteins; Signal Transduction
PubMed: 22094470
DOI: 10.1152/ajpendo.00333.2011 -
Rheumatology (Oxford, England) Dec 2016Prolactin (PRL) is a lactation-inducing hormone with immunomodulatory properties and is found at elevated levels in the serum of patients with RA and other rheumatic...
OBJECTIVES
Prolactin (PRL) is a lactation-inducing hormone with immunomodulatory properties and is found at elevated levels in the serum of patients with RA and other rheumatic diseases. The PRL receptor (PRLR) has been shown to be expressed by macrophages in atherosclerotic plaques. The aim of this study was to examine PRLR expression by synovial macrophages and its role in the regulation of macrophage activation.
METHODS
Serum monomeric 23 kDa PRL levels were measured in 119 RA patients using a fluoroimmunometric assay. PRLR expression was assessed in synovial tissue of 91 RA, 15 PsA and 8 OA patients by immunohistochemistry and digital image analysis. Double IF was used to identify PRLR-expressing cells. The effects of PRL on monocyte-derived macrophage gene expression were examined by quantitative real-time PCR and ELISA.
RESULTS
Serum PRL levels were similar in female and male RA patients. Median (interquartile range) PRLR expression was significantly higher (P < 0.05) in RA and PsA synovial tissue compared with OA. PRLR colocalized with synovial CD68 macrophages and von Willebrand factor endothelial cells. In vitro, PRLR was prominently expressed in IFN-γ-and IL-10-polarized macrophages compared with other polarizing conditions. PRL by itself had negligible effects on macrophage gene expression, but cooperated with CD40L and TNF to increase expression of pro-inflammatory genes including IL-6, IL-8 and IL-12β.
CONCLUSIONS
Synovial PRLR expression is enhanced in patients with inflammatory arthritis compared with OA, and PRL cooperates with other pro-inflammatory stimuli to activate macrophages. These results identify PRL and PRLR as potential new therapeutic targets in inflammatory arthritis.
Topics: Antigens, CD; Arthritis, Psoriatic; Arthritis, Rheumatoid; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; Humans; Macrophage Activation; Macrophages; Male; Middle Aged; RNA, Messenger; Real-Time Polymerase Chain Reaction; Receptors, Prolactin; Synovial Membrane; Up-Regulation
PubMed: 27616146
DOI: 10.1093/rheumatology/kew316 -
The Oncologist May 2016Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical...
LESSONS LEARNED
Despite evidence for a role for prolactin signaling in breast and prostate tumorigenesis, a prolactin receptor-binding monoclonal antibody has not produced clinical efficacy.Increased serum prolactin levels may be a biomarker for prolactin receptor inhibition.Results from the pharmacokinetic and pharmacodynamics (PD) studies suggest that inappropriately long dosing intervals and insufficient exposure to LFA102 may have resulted in lack of antitumor efficacy.Based on preclinical data, combination therapy of LFA102 with those novel agents targeting hormonal pathways in metastatic castration-resistant prostate cancer and metastatic breast cancer is promising.Given the PD evidence of prolactin receptor blockade by LFA102, this drug has the potential to be used in conditions such as hyperprolactinemia that are associated with high prolactin levels.
BACKGROUND
Prolactin receptor (PRLR) signaling is implicated in breast and prostate cancer. LFA102, a humanized monoclonal antibody (mAb) that binds to and inhibits the PRLR, has exhibited promising preclinical antitumor activity.
METHODS
Patients with PRLR-positive metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) received doses of LFA102 at 3-60 mg/kg intravenously once every 4 weeks. Objectives were to determine the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) to investigate the safety/tolerability of LFA102 and to assess pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.
RESULTS
A total of 73 patients were enrolled at 5 dose levels. The MTD was not reached because of lack of dose-limiting toxicities. The RDE was established at 60 mg/kg based on PK and PD analysis and safety data. The most common all-cause adverse events (AEs) were fatigue (44%) and nausea (33%) regardless of relationship. Grade 3/4 AEs reported to be related to LFA102 occurred in 4% of patients. LFA102 exposure increased approximately dose proportionally across the doses tested. Serum prolactin levels increased in response to LFA102 administration, suggesting its potential as a biomarker for PRLR inhibition. No antitumor activity was detected.
CONCLUSION
Treatment with LFA102 was safe and well tolerated, but did not show antitumor activity as monotherapy at the doses tested.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Prostatic Neoplasms, Castration-Resistant; Receptors, Prolactin
PubMed: 27091421
DOI: 10.1634/theoncologist.2015-0502 -
The Journal of Biological Chemistry Apr 2017Cell-surface cytokine receptors are regulated by their -interacting stimulatory and inhibitory co-receptors. We previously showed that the Ig-like cell-adhesion molecule...
Cell-surface cytokine receptors are regulated by their -interacting stimulatory and inhibitory co-receptors. We previously showed that the Ig-like cell-adhesion molecule nectin-4 -interacts with the prolactin receptor through the extracellular region and stimulates prolactin-induced prolactin receptor activation and signaling, resulting in alveolar development in the mouse mammary gland. However, it remains unknown how this interaction stimulates these effects. We show here that the -interaction of the extracellular region of nectin-4 with the prolactin receptor was not sufficient for eliciting these effects and that the cytoplasmic region of nectin-4 was also required for this interaction. The cytoplasmic region of nectin-4 directly interacted with suppressor of cytokine signaling 1 (SOCS1), but not SOCS3, JAK2, or STAT5a, and inhibited the interaction of SOCS1 with JAK2, eventually resulting in the increased phosphorylation of STAT5a. The juxtamembrane region of nectin-4 interacted with the Src homology 2 domain of SOCS1. Both the interaction of nectin-4 with the extracellular region of the prolactin receptor and the interaction of SOCS1 with the cytoplasmic region of nectin-4 were required for the stimulatory effect of nectin-4 on the prolactin-induced prolactin receptor activation. The third Ig-like domain of nectin-4 and the second fibronectin type III domain of the prolactin receptor were involved in this -interaction, and both the extracellular and transmembrane regions of nectin-4 and the prolactin receptor were required for this direct interaction. These results indicate that nectin-4 serves as a stimulatory co-receptor for the prolactin receptor by regulating the feedback inhibition of SOCS1 in the JAK2-STAT5a signaling pathway.
Topics: Animals; Cell Adhesion Molecules; Cytoplasm; Female; Fibronectins; Gene Expression Regulation; HEK293 Cells; Humans; Janus Kinase 2; Mammary Glands, Animal; Mice; Mutation; Phosphorylation; Prolactin; Receptors, Prolactin; STAT5 Transcription Factor; Signal Transduction; Suppressor of Cytokine Signaling 1 Protein; Tumor Suppressor Proteins
PubMed: 28258213
DOI: 10.1074/jbc.M116.769091