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Development of a reliable automated screening system to identify small molecules and biologics that promote human β-cell regeneration.
Aamodt KI, Aramandla R, Brown JJ, Fiaschi-Taesch N, Wang P, Stewart AF, Brissova M, Powers AC
(2016) Am J Physiol Endocrinol Metab 311: E859-E868
MeSH Terms: Activins, Adenosine, Adenosine A2 Receptor Agonists, Adenosine-5'-(N-ethylcarboxamide), Adult, Automation, Cell Culture Techniques, Cell Proliferation, Drug Evaluation, Preclinical, Erythropoietin, Exenatide, Female, GABA Agents, Harmine, Humans, Incretins, Insulin-Secreting Cells, Male, Middle Aged, Monoamine Oxidase Inhibitors, Myostatin, Nucleosides, Peptides, Platelet-Derived Growth Factor, Prolactin, Regeneration, Serotonin, Serotonin Receptor Agonists, Vasodilator Agents, Venoms, Young Adult, gamma-Aminobutyric Acid
Show Abstract · Added April 26, 2017
Numerous compounds stimulate rodent β-cell proliferation; however, translating these findings to human β-cells remains a challenge. To examine human β-cell proliferation in response to such compounds, we developed a medium-throughput in vitro method of quantifying adult human β-cell proliferation markers. This method is based on high-content imaging of dispersed islet cells seeded in 384-well plates and automated cell counting that identifies fluorescently labeled β-cells with high specificity using both nuclear and cytoplasmic markers. β-Cells from each donor were assessed for their function and ability to enter the cell cycle by cotransduction with adenoviruses encoding cell cycle regulators cdk6 and cyclin D3. Using this approach, we tested 12 previously identified mitogens, including neurotransmitters, hormones, growth factors, and molecules, involved in adenosine and Tgf-1β signaling. Each compound was tested in a wide concentration range either in the presence of basal (5 mM) or high (11 mM) glucose. Treatment with the control compound harmine, a Dyrk1a inhibitor, led to a significant increase in Ki-67 β-cells, whereas treatment with other compounds had limited to no effect on human β-cell proliferation. This new scalable approach reduces the time and effort required for sensitive and specific evaluation of human β-cell proliferation, thus allowing for increased testing of candidate human β-cell mitogens.
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32 MeSH Terms
Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells.
Banerjee RR, Cyphert HA, Walker EM, Chakravarthy H, Peiris H, Gu X, Liu Y, Conrad E, Goodrich L, Stein RW, Kim SK
(2016) Diabetes 65: 2331-41
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Cyclin A2, Cyclin B1, Cyclin B2, Cyclin D1, Cyclin D2, Diabetes, Gestational, Female, Forkhead Box Protein M1, Insulin, Insulin-Secreting Cells, MafB Transcription Factor, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pregnancy, Receptors, Prolactin, Serotonin, Signal Transduction, Tryptophan Hydroxylase
Show Abstract · Added September 19, 2016
β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
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23 MeSH Terms
Impaired islet function in commonly used transgenic mouse lines due to human growth hormone minigene expression.
Brouwers B, de Faudeur G, Osipovich AB, Goyvaerts L, Lemaire K, Boesmans L, Cauwelier EJ, Granvik M, Pruniau VP, Van Lommel L, Van Schoors J, Stancill JS, Smolders I, Goffin V, Binart N, in't Veld P, Declercq J, Magnuson MA, Creemers JW, Schuit F, Schraenen A
(2014) Cell Metab 20: 979-90
MeSH Terms: Animals, Female, Human Growth Hormone, Humans, Islets of Langerhans, Male, Mice, Mice, Transgenic, Receptors, Prolactin, Tryptophan Hydroxylase
Show Abstract · Added December 11, 2014
The human growth hormone (hGH) minigene is frequently used in the derivation of transgenic mouse lines to enhance transgene expression. Although this minigene is present in the transgenes as a secondcistron, and thus not thought to be expressed, we found that three commonly used lines, Pdx1-Cre(Late), RIP-Cre, and MIP-GFP, each expressed significant amounts of hGH in pancreatic islets. Locally secreted hGH binds to prolactin receptors on β cells, activates STAT5 signaling, and induces pregnancy-like changes in gene expression, thereby augmenting pancreatic β cell mass and insulin content. In addition, islets of Pdx1-Cre(Late) mice have lower GLUT2 expression and reduced glucose-induced insulin release and are protected against the β cell toxin streptozotocin. These findings may be important when interpreting results obtained when these and other hGH minigene-containing transgenic mice are used.
Copyright © 2014 Elsevier Inc. All rights reserved.
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10 MeSH Terms
The activity of prolactin releasing peptide correlates with its helicity.
Deluca SH, Rathmann D, Beck-Sickinger AG, Meiler J
(2013) Biopolymers 99: 314-25
MeSH Terms: Amino Acid Sequence, Animals, Binding Sites, COS Cells, Cell Line, Tumor, Cercopithecus aethiops, Circular Dichroism, Humans, Hydrogen-Ion Concentration, Magnetic Resonance Spectroscopy, Models, Molecular, Molecular Sequence Data, Mutation, Prolactin-Releasing Hormone, Protein Binding, Protein Conformation, Protein Stability, Protein Structure, Secondary, Receptors, Neuropeptide, Signal Transduction, Sodium Dodecyl Sulfate, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Temperature, Trifluoroacetic Acid
Show Abstract · Added January 24, 2015
The prolactin releasing peptide (PrRP) is involved in regulating food intake and body weight homeostasis, but molecular details on the activation of the PrRP receptor remain unclear. C-terminal segments of PrRP with 20 (PrRP20) and 13 (PrRP8-20) amino acids, respectively, have been suggested to be fully active. The data presented herein indicate this is true for the wildtype receptor only; a 5-10-fold loss of activity was found for PrRP8-20 compared to PrRP20 at two extracellular loop mutants of the receptor. To gain insight into the secondary structure of PrRP, we used CD spectroscopy performed in TFE and SDS. Additionally, previously reported NMR data, combined with ROSETTANMR, were employed to determine the structure of amidated PrRP20. The structural ensemble agrees with the spectroscopic data for the full-length peptide, which exists in an equilibrium between α- and 3(10)-helix. We demonstrate that PrRP8-20's reduced propensity to form an α-helix correlates with its reduced biological activity on mutant receptors. Further, distinct amino acid replacements in PrRP significantly decrease affinity and activity but have no influence on the secondary structure of the peptide. We conclude that formation of a primarily α-helical C-terminal region of PrRP is critical for receptor activation.
Copyright © 2012 Wiley Periodicals, Inc.
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24 MeSH Terms
Ligand-mimicking receptor variant discloses binding and activation mode of prolactin-releasing peptide.
Rathmann D, Lindner D, DeLuca SH, Kaufmann KW, Meiler J, Beck-Sickinger AG
(2012) J Biol Chem 287: 32181-94
MeSH Terms: Amino Acid Sequence, Animals, COS Cells, Cercopithecus aethiops, Cloning, Molecular, Drug Design, Genetic Vectors, HEK293 Cells, Humans, Inhibitory Concentration 50, Ligands, Molecular Sequence Data, Mutagenesis, Mutation, Peptides, Prolactin, Prolactin-Releasing Hormone, Protein Binding, Receptors, G-Protein-Coupled, Sequence Homology, Amino Acid, Signal Transduction
Show Abstract · Added January 24, 2015
The prolactin-releasing peptide receptor and its bioactive RF-amide peptide (PrRP20) have been investigated to explore the ligand binding mode of peptide G-protein-coupled receptors (GPCRs). By receptor mutagenesis, we identified the conserved aspartate in the upper transmembrane helix 6 (Asp(6.59)) of the receptor as the first position that directly interacts with arginine 19 of the ligand (Arg(19)). Replacement of Asp(6.59) with Arg(19) of PrRP20 led to D6.59R, which turned out to be a constitutively active receptor mutant (CAM). This suggests that the mutated residue at the top of transmembrane helix 6 mimics Arg(19) by interacting with additional binding partners in the receptor. Next, we generated an initial comparative model of this CAM because no ligand docking was required, and we selected the next set of receptor mutants to find the engaged partners of the binding pocket. In an iterative process, we identified two acidic residues and two hydrophobic residues that form the peptide ligand binding pocket. As all residues are localized on top or in the upper part of the transmembrane domains, we clearly can show that the extracellular surface of the receptor is sufficient for full signal transduction for prolactin-releasing peptide, rather than a deep, membrane-embedded binding pocket. This contributes to the knowledge of the binding of peptide ligands to GPCRs and might facilitate the development of GPCR ligands, but it also provides new targeting of CAMs involved in hereditary diseases.
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21 MeSH Terms
Maternal and cord blood hormone levels in the United States and China and the intrauterine origin of breast cancer.
Lagiou P, Samoli E, Okulicz W, Xu B, Lagiou A, Lipworth L, Georgila C, Vatten L, Adami HO, Trichopoulos D, Hsieh CC
(2011) Ann Oncol 22: 1102-8
MeSH Terms: Adiponectin, Adult, Breast Neoplasms, China, Female, Fetal Blood, Gonadal Steroid Hormones, Hormones, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor Binding Proteins, Insulin-Like Growth Factor I, Pregnancy, Prolactin, Sex Hormone-Binding Globulin, Statistics, Nonparametric, United States, Young Adult
Show Abstract · Added March 1, 2014
BACKGROUND - Breast cancer is less common in China than in the United States and perinatal characteristics predict breast cancer risk in the offspring. We determined levels of pregnancy hormones in Boston and Shanghai to identify those possibly involved in the intrauterine origin of breast cancer.
PARTICIPANTS AND METHODS - We compared maternal and cord blood levels of estradiol, estriol, testosterone, progesterone, prolactin, insulin-like growth factors (IGF) 1 and 2, insulin-like growth factor-binding protein 3, adiponectin and sex hormone-binding globulin (SHBG) in 241 Caucasian and 295 Chinese women.
RESULTS - In both centers, hormone levels at the 16th were predictive of those at the 27th gestational week, but there was little correlation between maternal and cord blood levels. In cord blood, we found significantly (P < 0.01) higher levels of estradiol (44.2%), testosterone (54.5%), IGF-2 (22.7%) and strikingly SHBG (104.6%) in Shanghai women, whereas the opposite was true for IGF-1 (-36.8%).
CONCLUSIONS - Taking into account the current understanding of the plausible biological role of the examined endocrine factors, those likely to be involved in the intrauterine origin of breast cancer are SHBG and IGF-2, with higher cord blood levels among Chinese, and IGF-1, with higher cord blood levels among Caucasian women.
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18 MeSH Terms
Prevalence of valvular heart disease in a cohort of patients taking cabergoline for management of hyperprolactinemia.
Devin JK, Lakhani VT, Byrd BF, Blevins LS
(2008) Endocr Pract 14: 672-7
MeSH Terms: Adult, Cabergoline, Cohort Studies, Echocardiography, Ergolines, Female, Heart Valve Diseases, Humans, Hyperprolactinemia, Male, Middle Aged
Show Abstract · Added December 10, 2013
OBJECTIVE - To determine the prevalence of valvular heart disease in a cohort of patients taking cabergoline for the management of hyperprolactinemia.
METHODS - A retrospective review of medical records identified patients with hyperprolactinemia who underwent evaluation at Vanderbilt University Medical Center between January and June 2007. The medical records of those patients who were prescribed cabergoline and who underwent elective echocardiography were reviewed for details pertaining to cardiac valvular abnormalities and cabergoline use.
RESULTS - Forty-five patients (mean age, 41 +/- 10 years [SD]) taking 0.91 +/- 0.96 mg of cabergoline per week for a mean duration of 39 +/- 29 months underwent echocardiography. Abnormalities of the cardiac valves were present in 3 patients (7%): 1 patient exhibited mild mitral regurgitation, 1 patient had focal aortic valve thickening, and 1 patient demonstrated mitral valve thickening. We found no significant difference in either the cumulative dose of cabergoline (P = .800) or the duration of cabergoline therapy (P = .745) between those patients with and those without these echocardiographic abnormalities.
CONCLUSION - We found echocardiographic valve abnormalities in 3 of 45 patients (7%) who had been prescribed cabergoline for the management of hyperprolactinemia. This prevalence of valvular heart disease after approximately 3 years of cabergoline treatment is no different from that previously reported in normal populations as determined by echocardiography.
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11 MeSH Terms
Prolactin and ErbB4/HER4 signaling interact via Janus kinase 2 to induce mammary epithelial cell gene expression differentiation.
Muraoka-Cook RS, Sandahl M, Hunter D, Miraglia L, Earp HS
(2008) Mol Endocrinol 22: 2307-21
MeSH Terms: Animals, Cell Differentiation, Cell Line, Enzyme Activation, Epithelial Cells, ErbB Receptors, Female, Gene Expression Regulation, Heparin-binding EGF-like Growth Factor, Intercellular Signaling Peptides and Proteins, Janus Kinase 2, Mammary Glands, Animal, Mice, Phosphorylation, Pregnancy, Prolactin, Receptor, ErbB-4, Receptors, Prolactin, STAT5 Transcription Factor, Signal Transduction, Tyrosine
Show Abstract · Added March 5, 2014
Differentiation of mammary epithelium in vivo requires signaling through prolactin and ErbB4/HER4-dependent mechanisms. Although stimulation of either the prolactin receptor or ErbB4/HER4 results in activation of the transcription factor signal transducer and activator of transcription 5A (STAT5A) and induction of lactogenic differentiation, how these pathways intersect is unknown. We show herein that prolactin signaling in breast cells cooperates with and is substantially enhanced by the receptor tyrosine kinase ErbB4/HER4. Prolactin and the ErbB4/HER4 ligand heparin-binding epidermal growth factor each induced STAT5A tyrosine phosphorylation and nuclear translocation; each pathway required the intracellular tyrosine kinase Janus kinase 2 (JAK2). We found that full prolactin-mediated STAT5A activation and binding to the endogenous beta-casein promoter required ErbB4/HER4 but did not require ErbB1/epidermal growth factor receptor. For example, prolactin-induced STAT5A activity was markedly diminished in cells overexpressing kinase inactive HER4, in cells transfected with small interfering RNAs to specifically knock down endogenous ErbB4/HER4 expression and in cells treated with a small molecule inhibitor that targets ErbB4 kinase. Interestingly, prolactin caused ErbB4/HER4 tyrosine phosphorylation in a JAK2 kinase-dependent manner. Finally, prolactin receptor, ErbB4/HER4, and JAK2 were coimmunoprecipitated from prolactin-treated but not untreated cells. These results suggest that prolactin signaling engages the ErbB4 pathway via JAK2 and that ErbB4 provides an important component of STAT5A-dependent lactogenic differentiation; this pathway integration may help explain the similar deficit in mammary development observed in gene-targeted mice deficient in prolactin receptor, JAK2, ErbB4, or STAT5A.
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21 MeSH Terms
Acute myeloid leukemia-associated Mkl1 (Mrtf-a) is a key regulator of mammary gland function.
Sun Y, Boyd K, Xu W, Ma J, Jackson CW, Fu A, Shillingford JM, Robinson GW, Hennighausen L, Hitzler JK, Ma Z, Morris SW
(2006) Mol Cell Biol 26: 5809-26
MeSH Terms: Animals, Animals, Newborn, Apoptosis, Child, Failure to Thrive, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Targeting, Heart, Humans, Infant, Lactation, Leukemia, Megakaryoblastic, Acute, Male, Mammary Glands, Animal, Mice, Mice, Inbred C57BL, Mice, Knockout, Milk, Myocytes, Cardiac, Oligonucleotide Array Sequence Analysis, Oxytocin, Pregnancy, Prolactin, STAT3 Transcription Factor, Serum Response Factor, Trans-Activators
Show Abstract · Added March 5, 2014
Transcription of immediate-early genes--as well as multiple genes affecting muscle function, cytoskeletal integrity, apoptosis control, and wound healing/angiogenesis--is regulated by serum response factor (Srf). Extracellular signals regulate Srf in part via a pathway involving megakaryoblastic leukemia 1 (Mkl1, also known as myocardin-related transcription factor A [Mrtf-a]), which coactivates Srf-responsive genes downstream of Rho GTPases. Here we investigate Mkl1 function using gene targeting and show the protein to be essential for the physiologic preparation of the mammary gland during pregnancy and the maintenance of lactation. Lack of Mkl1 causes premature involution and impairs expression of Srf-dependent genes in the mammary myoepithelial cells, which control milk ejection following oxytocin-induced contraction. Despite the importance of Srf in multiple transcriptional pathways and widespread Mkl1 expression, the spectrum of abnormalities associated with Mkl1 absence appears surprisingly restricted.
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28 MeSH Terms
Characterization of a naturally-occurring polymorphism in the UHR-1 gene encoding the putative rat prolactin-releasing peptide receptor.
Ellacott KL, Donald EL, Clarkson P, Morten J, Masters D, Brennand J, Luckman SM
(2005) Peptides 26: 675-81
MeSH Terms: Animals, Base Sequence, DNA Primers, Hypothalamic Hormones, Molecular Sequence Data, Neuropeptides, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Prolactin-Releasing Hormone, Rats, Rats, Sprague-Dawley, Receptors, G-Protein-Coupled, Receptors, Neuropeptide, Species Specificity
Show Abstract · Added December 10, 2013
The rat orphan receptor UHR-1 and its human orthologue, GPR10, were first isolated in 1995. The ligand for this receptor, prolactin-releasing peptide (PrRP), was identified in 1998 by reverse pharmacology and has subsequently been implicated in a number of physiological processes. As supported by its localization and regulation in the hypothalamus and brainstem, we have shown previously that PrRP is involved in energy homeostasis. Here we describe a naturally occurring polymorphism in the UHR-1 gene that results in an ATG to ATA change at the putative translational initiation site. The presence of the polymorphism abolished the binding of 125I PrRP in rat brain slices but did not affect the ability of PrRP to reduce fast-induced food intake. Together this data suggest that PrRP may be exerting its feeding effects through a receptor other than UHR-1.
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14 MeSH Terms