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Results: 1 to 8 of 8

Publication Record


Age-dependent human β cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling.
Dai C, Hang Y, Shostak A, Poffenberger G, Hart N, Prasad N, Phillips N, Levy SE, Greiner DL, Shultz LD, Bottino R, Kim SK, Powers AC
(2017) J Clin Invest 127: 3835-3844
MeSH Terms: Adult, Aging, Animals, Calcineurin, Cyclin A1, Exenatide, Female, Forkhead Box Protein M1, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Male, Mice, Inbred NOD, Middle Aged, NFATC Transcription Factors, Peptides, Signal Transduction, Venoms
Show Abstract · Added March 29, 2020
Inadequate pancreatic β cell function underlies type 1 and type 2 diabetes mellitus. Strategies to expand functional cells have focused on discovering and controlling mechanisms that limit the proliferation of human β cells. Here, we developed an engraftment strategy to examine age-associated human islet cell replication competence and reveal mechanisms underlying age-dependent decline of β cell proliferation in human islets. We found that exendin-4 (Ex-4), an agonist of the glucagon-like peptide 1 receptor (GLP-1R), stimulates human β cell proliferation in juvenile but not adult islets. This age-dependent responsiveness does not reflect loss of GLP-1R signaling in adult islets, since Ex-4 treatment stimulated insulin secretion by both juvenile and adult human β cells. We show that the mitogenic effect of Ex-4 requires calcineurin/nuclear factor of activated T cells (NFAT) signaling. In juvenile islets, Ex-4 induced expression of calcineurin/NFAT signaling components as well as target genes for proliferation-promoting factors, including NFATC1, FOXM1, and CCNA1. By contrast, expression of these factors in adult islet β cells was not affected by Ex-4 exposure. These studies reveal age-dependent signaling mechanisms regulating human β cell proliferation, and identify elements that could be adapted for therapeutic expansion of human β cells.
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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
Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice.
Scheving LA, Zhang X, Stevenson MC, Threadgill DW, Russell WE
(2015) Am J Physiol Gastrointest Liver Physiol 308: G364-77
MeSH Terms: Animals, Carbon Tetrachloride, Chemical and Drug Induced Liver Injury, Cyclin A, Cyclin D1, Epidermal Growth Factor, ErbB Receptors, Hepatocytes, Liver Regeneration, Mice, Neuregulin-1, Proto-Oncogene Proteins c-met, Receptor, ErbB-3
Show Abstract · Added May 5, 2016
The role(s) of the epidermal growth factor receptor (EGFR) in hepatocytes is unknown. We generated a murine hepatocyte specific-EGFR knockout (KO) model to evaluate how loss of hepatocellular EGFR expression affects processes such as EGF clearance, circulating EGF concentrations, and liver regeneration following 70% resection or CCl4-induced centrilobular injury. We were able to disrupt EGFR expression effectively in hepatocytes and showed that the ability of EGF and heregulin (HRG) to phosphorylate EGFR and ERBB3, respectively, required EGFR. Loss of hepatocellular EGFR impaired clearance of exogenous EGF from the portal circulation but paradoxically resulted in reduced circulating levels of endogenous EGF. This was associated with decreased submandibular salivary gland production of EGF. EGFR disruption did not result in increased expression of other ERBB proteins or Met, except in neonatal mice. Liver regeneration following 70% hepatectomy revealed a mild phenotype, with no change in cyclin D1 expression and slight differences in cyclin A expression compared with controls. Peak 5-bromo-2'-deoxyuridine labeling was shifted from 36 to 48 h. Centrilobular damage and regenerative response induced by carbon tetrachloride (CCl4) were identical in the KO and wild-type mice. In contrast, loss of Met increased CCl4-induced necrosis and delayed regeneration. Although loss of hepatocellular EGFR alone did not have an effect in this model, EGFR-Met double KOs displayed enhanced necrosis and delayed liver regeneration compared with Met KOs alone. This suggests that EGFR and Met may partially compensate for the loss of the other, although other compensatory mechanisms can be envisioned.
Copyright © 2015 the American Physiological Society.
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13 MeSH Terms
Phosphorylation of Rad9 at serine 328 by cyclin A-Cdk2 triggers apoptosis via interfering Bcl-xL.
Zhan Z, He K, Zhu D, Jiang D, Huang YH, Li Y, Sun C, Jin YH
(2012) PLoS One 7: e44923
MeSH Terms: Active Transport, Cell Nucleus, Apoptosis, Biocatalysis, Cell Cycle Proteins, Cell Nucleus, Cyclin A, Cyclin-Dependent Kinase 2, Etoposide, HeLa Cells, Humans, Mitochondria, Phosphorylation, RNA Interference, Serine, Signal Transduction, Topoisomerase II Inhibitors, Up-Regulation, bcl-X Protein
Show Abstract · Added July 28, 2015
Cyclin A-Cdk2, a cell cycle regulated Ser/Thr kinase, plays important roles in a variety of apoptoticprocesses. However, the mechanism of cyclin A-Cdk2 regulated apoptosis remains unclear. Here, we demonstrated that Rad9, a member of the BH3-only subfamily of Bcl-2 proteins, could be phosphorylated by cyclin A-Cdk2 in vitro and in vivo. Cyclin A-Cdk2 catalyzed the phosphorylation of Rad9 at serine 328 in HeLa cells during apoptosis induced by etoposide, an inhibitor of topoisomeraseII. The phosphorylation of Rad9 resulted in its translocation from the nucleus to the mitochondria and its interaction with Bcl-xL. The forced activation of cyclin A-Cdk2 in these cells by the overexpression of cyclin A,triggered Rad9 phosphorylation at serine 328 and thereby promoted the interaction of Rad9 with Bcl-xL and the subsequent initiation of the apoptotic program. The pro-apoptotic effects regulated by the cyclin A-Cdk2 complex were significantly lower in cells transfected with Rad9S328A, an expression vector that encodes a Rad9 mutant that is resistant to cyclin A-Cdk2 phosphorylation. These findings suggest that cyclin A-Cdk2 regulates apoptosis through a mechanism that involves Rad9phosphorylation.
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18 MeSH Terms
Expression patterns and cell cycle profiles of PCNA, MCM6, cyclin D1, cyclin A2, cyclin B1, and phosphorylated histone H3 in the developing mouse retina.
Barton KM, Levine EM
(2008) Dev Dyn 237: 672-82
MeSH Terms: Animals, Cell Cycle, Cell Cycle Proteins, Cyclin A, Cyclin A2, Cyclin B, Cyclin B1, Cyclin D, Cyclins, Histones, Mice, Minichromosome Maintenance Complex Component 6, Phosphorylation, Proliferating Cell Nuclear Antigen, Retina
Show Abstract · Added November 2, 2015
A challenge in studying organogenesis is the ability to identify progenitor cell populations. To address this problem, we characterized the expression patterns of cell cycle proteins during mouse retinal development and used flow cytometry to determine the expression profiles in the cell cycle. We found that MCM6 and PCNA are expressed in essentially all retinal progenitor cells throughout the proliferative period and these proteins are readily detectable in all cell cycle phases. Furthermore, their expression levels are downregulated as cells exit the cell cycle and differentiate. We also analyzed the expression of Cyclins D1, A2, and B1, and phosphorylated Histone H3 and found unexpected expression patterns and cell cycle profiles. The combined utilization of the markers tested and the use of flow cytometry should further facilitate the study of stem and progenitor cell behavior during development and in adult tissues.
(c) 2008 Wiley-Liss, Inc.
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15 MeSH Terms
Human origin recognition complex large subunit is degraded by ubiquitin-mediated proteolysis after initiation of DNA replication.
Méndez J, Zou-Yang XH, Kim SY, Hidaka M, Tansey WP, Stillman B
(2002) Mol Cell 9: 481-91
MeSH Terms: Animals, Cell Cycle, Cell Cycle Proteins, Cell Fractionation, Chromatin, Cyclin A, Cysteine Endopeptidases, DNA Damage, DNA Replication, DNA-Binding Proteins, Flow Cytometry, Gene Silencing, HeLa Cells, Humans, Macromolecular Substances, Multienzyme Complexes, Origin Recognition Complex, Phosphorylation, Proteasome Endopeptidase Complex, Protein Subunits, Recombinant Fusion Proteins, S-Phase Kinase-Associated Proteins, Ubiquitin
Show Abstract · Added March 10, 2014
Eukaryotic cells possess overlapping mechanisms to ensure that DNA replication is restricted to the S phase of the cell cycle. The levels of hOrc1p, the largest subunit of the human origin recognition complex, vary during the cell division cycle. In rapidly proliferating cells, hOrc1p is expressed and targeted to chromatin as cells exit mitosis and prereplicative complexes are formed. Later, as cyclin A accumulates and cells enter S phase, hOrc1p is ubiquitinated on chromatin and then degraded. hOrc1p destruction occurs through the proteasome and is signaled in part by the SCF(Skp2) ubiquitin-ligase complex. Other hORC subunits are stable throughout the cell cycle. The regulation of hOrc1p may be an important mechanism in maintaining the ploidy in human cells.
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23 MeSH Terms
Inhibition of pRb phosphorylation and cell cycle progression by an antennapedia-p16(INK4A) fusion peptide in pancreatic cancer cells.
Fujimoto K, Hosotani R, Miyamoto Y, Doi R, Koshiba T, Otaka A, Fujii N, Beauchamp RD, Imamura M
(2000) Cancer Lett 159: 151-8
MeSH Terms: Amino Acid Sequence, Antennapedia Homeodomain Protein, Biotinylation, Carrier Proteins, Cell Cycle, Cell Division, Cyclin A, Cyclin-Dependent Kinase Inhibitor p16, Dose-Response Relationship, Drug, Homeodomain Proteins, Humans, Molecular Sequence Data, Nuclear Proteins, Pancreatic Neoplasms, Phosphorylation, Recombinant Fusion Proteins, Retinoblastoma Protein, Transcription Factors, Tumor Cells, Cultured
Show Abstract · Added June 14, 2013
In this study, we examined whether or not a small peptide derived from p16(INK4A) protein with the antennapedia carrier sequence could inhibit the growth of pancreatic cancer cells through the inhibition of cell cycle progression. Growth inhibition by the p16-derived peptide was observed in a time- and dose-dependent manner in AsPC-1 and BxPC-3 cells (p16-negative and pRb-positive), whereas Saos-2 cells (p16-positive and pRb-negative) showed no inhibitory effect. In AsPC-1 and BxPC-3 cells, the proportion of cells in the G(1) phase markedly increased 48 h after treatment with 20 microM p16-derived peptide. Cell-cycle analysis of Saos-2 cells showed little change during the entire period of treatment. Immunoblot analysis showed inhibition of pRb phosphorylation after treatment of BxPC-3 with 10 microM p16 peptide. Furthermore, the p16 peptide caused a decrease in cyclin A at later times of treatment. These results demonstrate that the p16-derived peptide can inhibit the growth of p16-negative and pRb-positive pancreatic cancer cells by means of G(1) phase cell cycle arrest resulting from the inhibition of pRb phosphorylation. Restoration of p16/pRb tumor-suppressive pathway by re-expression of p16(INK4A) may play a therapeutic role in the treatment of pancreatic cancer.
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19 MeSH Terms
Salicylate-induced growth arrest is associated with inhibition of p70s6k and down-regulation of c-myc, cyclin D1, cyclin A, and proliferating cell nuclear antigen.
Law BK, Waltner-Law ME, Entingh AJ, Chytil A, Aakre ME, Nørgaard P, Moses HL
(2000) J Biol Chem 275: 38261-7
MeSH Terms: Acetaminophen, Analgesics, Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Cell Division, Cell Line, Cyclin A, Cyclin D1, Epidermal Growth Factor, Gene Expression Regulation, Genes, myc, Humans, Indomethacin, Insulin-Like Growth Factor I, Mice, Mitogen-Activated Protein Kinases, Proliferating Cell Nuclear Antigen, Proto-Oncogene Proteins c-myc, Ribosomal Protein S6 Kinases, Salicylates, Tetradecanoylphorbol Acetate, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added February 17, 2014
Salicylate and its pro-drug form aspirin are widely used medicinally for their analgesic and anti-inflammatory properties, and more recently for their ability to protect against colon cancer and cardiovascular disease. Despite the wide use of salicylate, the mechanisms underlying its biological activities are largely unknown. Recent reports suggest that salicylate may produce some of its effects by modulating the activities of protein kinases. Since we have previously shown that the farnesyltransferase inhibitor l-744, 832 inhibits cell proliferation and p70(s6k) activity, and salicylate inhibits cell proliferation, we examined whether salicylate affects p70(s6k) activity. We find that salicylate potently inhibits p70(s6k) activation and phosphorylation in a p38 MAPK-independent manner. Interestingly, low salicylate concentrations (/=5 mm) are required to block p70(s6k) activation by epidermal growth factor + insulin-like growth factor-1. These data suggest that salicylate may selectively inhibit p70(s6k) activation in response to specific stimuli. Inhibition of p70(s6k) by salicylate occurs within 5 min, is independent of the phosphatidylinositol 3-kinase pathway, and is associated with dephosphorylation of p70(s6k) on its major rapamycin-sensitive site, Thr(389). A rapamycin-resistant mutant of p70(s6k) is resistant to salicylate-induced Thr(389) dephosphorylation.
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23 MeSH Terms