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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
Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.
Peters U, Jiao S, Schumacher FR, Hutter CM, Aragaki AK, Baron JA, Berndt SI, Bézieau S, Brenner H, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Casey G, Chan AT, Chang-Claude J, Chanock SJ, Chen LS, Coetzee GA, Coetzee SG, Conti DV, Curtis KR, Duggan D, Edwards T, Fuchs CS, Gallinger S, Giovannucci EL, Gogarten SM, Gruber SB, Haile RW, Harrison TA, Hayes RB, Henderson BE, Hoffmeister M, Hopper JL, Hudson TJ, Hunter DJ, Jackson RD, Jee SH, Jenkins MA, Jia WH, Kolonel LN, Kooperberg C, Küry S, Lacroix AZ, Laurie CC, Laurie CA, Le Marchand L, Lemire M, Levine D, Lindor NM, Liu Y, Ma J, Makar KW, Matsuo K, Newcomb PA, Potter JD, Prentice RL, Qu C, Rohan T, Rosse SA, Schoen RE, Seminara D, Shrubsole M, Shu XO, Slattery ML, Taverna D, Thibodeau SN, Ulrich CM, White E, Xiang Y, Zanke BW, Zeng YX, Zhang B, Zheng W, Hsu L, Colon Cancer Family Registry and the Genetics and Epidemiology of Colorectal Cancer Consortium
(2013) Gastroenterology 144: 799-807.e24
MeSH Terms: Age Distribution, Aged, Aged, 80 and over, Colorectal Neoplasms, Cyclin D2, DNA-Binding Proteins, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Incidence, Laminin, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Risk Assessment, Sex Distribution, T-Box Domain Proteins
Show Abstract · Added March 10, 2014
BACKGROUND & AIMS - Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.
METHODS - We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.
RESULTS - Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).
CONCLUSIONS - In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.
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20 MeSH Terms
Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer.
Jia WH, Zhang B, Matsuo K, Shin A, Xiang YB, Jee SH, Kim DH, Ren Z, Cai Q, Long J, Shi J, Wen W, Yang G, Delahanty RJ, Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Colon Cancer Family Registry (CCFR), Ji BT, Pan ZZ, Matsuda F, Gao YT, Oh JH, Ahn YO, Park EJ, Li HL, Park JW, Jo J, Jeong JY, Hosono S, Casey G, Peters U, Shu XO, Zeng YX, Zheng W
(2013) Nat Genet 45: 191-6
MeSH Terms: Asian Continental Ancestry Group, Chromosomes, Human, Pair 12, Chromosomes, Human, Pair 20, Chromosomes, Human, Pair 5, Colorectal Neoplasms, Cyclin D2, European Continental Ancestry Group, Far East, Genetic Predisposition to Disease, Genetics, Population, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Odds Ratio, Polymorphism, Single Nucleotide, Principal Component Analysis
Show Abstract · Added March 18, 2014
To identify new genetic factors for colorectal cancer (CRC), we conducted a genome-wide association study in east Asians. By analyzing genome-wide data in 2,098 cases and 5,749 controls, we selected 64 promising SNPs for replication in an independent set of samples, including up to 5,358 cases and 5,922 controls. We identified four SNPs with association P values of 8.58 × 10(-7) to 3.77 × 10(-10) in the combined analysis of all east Asian samples. Three of the four were replicated in a study conducted in 26,060 individuals of European descent, with combined P values of 1.22 × 10(-10) for rs647161 (5q31.1), 6.64 × 10(-9) for rs2423279 (20p12.3) and 3.06 × 10(-8) for rs10774214 (12p13.32 near the CCND2 gene), derived from meta-analysis of data from both east Asian and European-ancestry populations. This study identified three new CRC susceptibility loci and provides additional insight into the genetics and biology of CRC.
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17 MeSH Terms
Cyclin D1 inactivation extends proliferation and alters histogenesis in the postnatal mouse retina.
Das G, Clark AM, Levine EM
(2012) Dev Dyn 241: 941-52
MeSH Terms: Animals, Cell Cycle, Cell Differentiation, Cell Proliferation, Cyclin D1, Cyclin D2, Cyclin D3, Mice, Mice, Knockout, Retina, Stem Cells
Show Abstract · Added November 2, 2015
BACKGROUND - The cell-cycle regulator Cyclin D1 is expressed in embryonic retinal progenitor cells (RPCs) and regulates their cell-cycle rate and neurogenic output. We report here that Cyclin D1 also has important functions in postnatal retinal histogenesis.
RESULTS - The initial production of Müller glia and bipolar cells was enhanced in Cyclin D1 knockout (Ccnd1(-/-) ) retinas. Despite a steeper than normal rate of depletion of the RPC population at embryonic ages, postnatal Ccnd1(-/-) retinas exhibited an extended window of proliferation, neurogenesis, and gliogenesis. Cyclin D3, normally confined to Müller glia, was prematurely expressed in Ccnd1(-/-) RPCs. However, Cyclin D3 did not compensate for Cyclin D1 in regulating cell-cycle kinetics or neurogenic output.
CONCLUSIONS - The data presented in this study along with our previous finding that Cyclin D2 was unable to completely compensate for the absence of Cyclin D1 indicate that Cyclin D1 regulates retinal histogenesis in ways not shared by the other D-cyclins.
Copyright © 2012 Wiley Periodicals, Inc.
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11 MeSH Terms
NF-κB inducing kinase (NIK) modulates melanoma tumorigenesis by regulating expression of pro-survival factors through the β-catenin pathway.
Thu YM, Su Y, Yang J, Splittgerber R, Na S, Boyd A, Mosse C, Simons C, Richmond A
(2012) Oncogene 31: 2580-92
MeSH Terms: Animals, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cyclin D2, Down-Regulation, Enzyme Activation, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, bcl-2, Genes, myc, Humans, Melanoma, Melanoma, Experimental, Mice, Neoplasm Metastasis, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Signal Transduction, beta Catenin
Show Abstract · Added June 14, 2013
Nuclear factor-κB (NF-κB) inducing kinase (NIK) is a MAP3K that regulates the activation of NF-κB. NIK is often highly expressed in tumor cells, including melanoma, but the significance of this in melanoma progression has been unclear. Tissue microarray analysis of NIK expression reveals that dysplastic nevi (n=22), primary (n=15) and metastatic melanoma (n=13) lesions showed a statistically significant elevation in NIK expression when compared with benign nevi (n=30). Moreover, when short hairpin RNA techniques were used to knock-down NIK, the resultant NIK-depleted melanoma cell lines exhibited decreased proliferation, increased apoptosis, delayed cell cycle progression and reduced tumor growth in a mouse xenograft model. As expected, when NIK was depleted there was decreased activation of the non-canonical NF-κB pathway, whereas canonical NF-κB activation remained intact. NIK depletion also resulted in reduced expression of genes that contribute to tumor growth, including CXCR4, c-MYC and c-MET, and pro-survival factors such as BCL2 and survivin. These changes in gene expression are not fully explained by the attenuation of the non-canonical NF-κB pathway. Shown here for the first time is the demonstration that NIK modulates β-catenin-mediated transcription to promote expression of survivin. NIK-depleted melanoma cells exhibited downregulation of survivin as well as other β-catenin regulated genes including c-MYC, c-MET and CCND2. These data indicate that NIK mediates both β-catenin and NF-κB regulated transcription to modulate melanoma survival and growth. Thus, NIK may be a promising therapeutic target for melanoma.
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21 MeSH Terms
Glucose regulates cyclin D2 expression in quiescent and replicating pancreatic β-cells through glycolysis and calcium channels.
Salpeter SJ, Klochendler A, Weinberg-Corem N, Porat S, Granot Z, Shapiro AM, Magnuson MA, Eden A, Grimsby J, Glaser B, Dor Y
(2011) Endocrinology 152: 2589-98
MeSH Terms: Animals, Calcium Channel Agonists, Calcium Channels, Cell Cycle, Cell Line, Cell Nucleus, Cell Proliferation, Cyclin D2, Diabetes Mellitus, Experimental, Enzyme Inhibitors, Gene Expression Regulation, Glucose, Glycolysis, Humans, Islets of Langerhans, Male, Mice, Mice, Inbred ICR, Mice, Transgenic, Organ Culture Techniques, RNA, Messenger
Show Abstract · Added January 8, 2012
Understanding the molecular triggers of pancreatic β-cell proliferation may facilitate the development of regenerative therapies for diabetes. Genetic studies have demonstrated an important role for cyclin D2 in β-cell proliferation and mass homeostasis, but its specific function in β-cell division and mechanism of regulation remain unclear. Here, we report that cyclin D2 is present at high levels in the nucleus of quiescent β-cells in vivo. The major regulator of cyclin D2 expression is glucose, acting via glycolysis and calcium channels in the β-cell to control cyclin D2 mRNA levels. Furthermore, cyclin D2 mRNA is down-regulated during S-G(2)-M phases of each β-cell division, via a mechanism that is also affected by glucose metabolism. Thus, glucose metabolism maintains high levels of nuclear cyclin D2 in quiescent β-cells and modulates the down-regulation of cyclin D2 in replicating β-cells. These data challenge the standard model for regulation of cyclin D2 during the cell division cycle and suggest cyclin D2 as a molecular link between glucose levels and β-cell replication.
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21 MeSH Terms
Inhibition of cell growth by TGF beta 1 is associated with inhibition of B-myb and cyclin A in both BALB/MK and Mv1Lu cells.
Satterwhite DJ, Aakre ME, Gorska AE, Moses HL
(1994) Cell Growth Differ 5: 789-99
MeSH Terms: Animals, Cell Division, Cell Line, Cyclin D1, Cyclin D2, Cyclins, Epithelial Cells, Epithelium, Gene Expression Regulation, Keratinocytes, Lung, Mice, Mice, Inbred BALB C, Mink, Mitogens, Oncogene Proteins, Oncogenes, RNA, Messenger, Transforming Growth Factor beta
Show Abstract · Added February 17, 2014
The concept of positive and negative regulation of normal cellular growth by diffusible factors is well illustrated by the effects of epidermal growth factor and transforming growth factor beta 1 (TGF beta 1) on mouse keratinocytes (MK) and mink lung epithelial cells (Mv1Lu). MK and Mv1Lu are nontransformed cell lines that reversibly arrest at a point in late G1 in response to TGF beta 1. Previously, we have shown that expression of the protooncogene c-myc is induced upon epidermal growth factor stimulation of quiescent MK and Mv1Lu cells and that transcriptional suppression of c-myc by TGF beta 1 treatment is important in the TGF beta 1 growth inhibition pathway. Using epidermal growth factor-stimulated synchronized MK and Mv1Lu cells, we have investigated the mRNA expression of a large number of growth factor-inducible genes that are critical regulators of growth in G1 and at the G1/S transition. These genes, often found to be dysregulated in cancer, include transcription factors as well as cyclins and their associated kinases, that promote growth, and tumor suppressor genes, that inhibit growth. As reported here, TGF beta 1 significantly inhibited mRNA expression of B-myb and cyclin A in both cell lines, suggesting that these may be important common downstream targets in the growth inhibition pathway. In contrast, the expression patterns of cyclins D1 and D2 and the transcription factors E2F1 and E2F2 were unaffected in MK cells treated with TGF beta 1 but were significantly inhibited in TGF beta 1-treated Mv1Lu cells. We cite the evidence suggesting that the inhibition of B-myb and cyclin A may contribute to the late G1 arrest caused by TGF beta 1 and that these events may be linked through the actions of the product of the retinoblastoma susceptibility gene (Rb) or an Rb family member.
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19 MeSH Terms