DOCSLIB.ORG

Cyclin D2 Is Essential for the Compensatory -Cell Hyperplastic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Cyclin D2 Is Essential for the Compensatory -Cell Hyperplastic ORIGINAL ARTICLE Cyclin D2 Is Essential for the Compensatory ␤-Cell Hyperplastic Response to Insulin Resistance in Rodents Senta Georgia,1 Charlotte Hinault,2 Dan Kawamori,2 Jiang Hu,2 John Meyer,2 Murtaza Kanji,1 Anil Bhushan,1 and Rohit N. Kulkarni2 OBJECTIVE—A major determinant of the progression from sufficient to maintain euglycemia up to a specific thresh- insulin resistance to the development of overt type 2 diabetes is old, and crossing the threshold correlates with impaired a failure to mount an appropriate compensatory ␤-cell hyperplas- fasting glucose and clinical diabetes (4). tic response to maintain normoglycemia. We undertook the While direct data in humans is lacking, studies in rodents present study to directly explore the significance of the cell cycle clearly indicate that ␤-cell mass adaptively expands to com- protein cyclin D2 in the expansion of ␤-cell mass in two different models of insulin resistance. pensate for both physiological and pathophysiological states of insulin resistance including pregnancy, onset of obesity, RESEARCH DESIGN AND METHODS—We created com- and high-fat feeding and after partial pancreatectomy pound knockouts by crossing mice deficient in cyclin D2 (D2KO) (5–9). Although the adaptation is dependent on alterations with either the insulin receptor substrate 1 knockout (IRS1KO) in both the number and size of ␤-cells and generation of mice or the insulin receptor liver-specific knockout mice ␤ (LIRKO), neither of which develops overt diabetes on its own new -cells from endogenous progenitors (10,11), recent because of robust compensatory ␤-cell hyperplasia. We pheno- studies point to replication as a primary mechanism for typed the double knockouts and used RT-qPCR and immunohis- the physiological maintenance of adult ␤-cell mass (12) tochemistry to examine ␤-cell mass. and in response to insulin resistance in both rodents and RESULTS—Both compound knockouts, D2KO/LIRKO and humans (9,12–15). D2KO/IRS1KO, exhibited insulin resistance and hyperinsulin- Replication is achieved by reentry of the ␤-cell into the emia and an absence of compensatory ␤-cell hyperplasia. How- cell cycle and relies on proteins regulating the G1 phase ever, the diabetic D2KO/LIRKO group rapidly succumbed early (13,16–19). Our previous work has established that cyclin compared with a relatively normal lifespan in the glucose- D2, a G1/S cell-cycle regulator, is necessary for the post- intolerant D2KO/IRS1KO mice. natal expansion of ␤-cell mass (13). In these studies, we CONCLUSIONS—This study provides direct genetic evidence observed that in the absence of cyclin D2, the diminished that cyclin D2 is essential for the expansion of ␤-cell mass in ␤-cell mass established during the neonatal remodeling response to a spectrum of insulin resistance and points to the period was inadequate to sufficiently respond to metabolic cell-cycle protein as a potential therapeutic target that can be demand for insulin in adult mice, leading to glucose harnessed for preventing and curing type 2 diabetes. Diabetes 59:987–996, 2010 intolerance but not frank diabetes (13). While these exper- iments indicate that cyclin D2 is important during early postnatal expansion of ␤-cells for the adult mouse to achieve its optimal ␤-cell mass, its importance in cell he maintenance of an adequate and functional expansion in response to a pathophysiological demand for pancreatic ␤-cell mass dictates the body’s ability insulin is not known. Considering these observations, we to compensate for insulin resistance. Recent explored whether a limited but adequate ␤-cell mass that studies in autopsy samples from humans re- is challenged by physiological stress would fall below a T ␤ ported expansion of -cell mass from infants through functional threshold required to maintain euglycemia, and adolescence that was largely due to increased islet size eventually to promote the development of diabetes, using (1). Further, humans with established type 2 diabetes cyclin D2 knockout mice. To this end, we created com- exhibit a deficit in ␤-cell mass in comparison with their pound double knockouts by breeding cyclin D2 (D2KO) nondiabetic cohorts (2,3). Interestingly, obese, nondia- mice with either mice that are deficient in insulin receptor betic patients express a wide range of ␤-cell mass that is substrate 1 (IRS1KO) (20,21) or mice with a knockout of the insulin receptor specifically in liver (LIRKO) (22). These models reflect the spectrum of insulin resistance From the 1Larry Hillblom Islet Research Center, University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, California; and the and glucose intolerance observed in humans but do not 2Joslin Diabetes Center and Department of Medicine, Harvard Medical develop frank diabetes in part because of compensatory School, Boston, Massachusetts. ␤ Corresponding author: Rohit N. Kulkarni, [email protected], -cell expansion that can increase from 3-fold (IRS1KO) to or Anil Bhushan, [email protected]. 30-fold (LIRKO) largely by replication of ␤-cells (21,23). Received 3 June 2009 and accepted 7 January 2010. Published ahead of print Our results indicate that both D2KO/LIRKO and D2KO/ at http://diabetes.diabetesjournals.org on 27 January 2010. DOI: 10.2337/ ␤ db09-0838. IRS1KO double-knockout mice fail to show a -cell com- S.G. and C.H. contributed equally to this study. pensatory response to insulin resistance, leading to overt © 2010 by the American Diabetes Association. Readers may use this article as diabetes that is secondary, in part, to a dramatic decrease long as the work is properly cited, the use is educational and not for profit, ␤ ␤ and the work is not altered. See http://creativecommons.org/licenses/by in -cell mass due to reduced -cell replication. These data -nc-nd/3.0/ for details. provide genetic evidence that cyclin D2 is essential for the The costs of publication of this article were defrayed in part by the payment of page ␤ charges. This article must therefore be hereby marked “advertisement” in accordance compensatory increase in -cell hyperplasia in response to with 18 U.S.C. Section 1734 solely to indicate this fact. insulin-resistant states. diabetes.diabetesjournals.org DIABETES, VOL. 59, APRIL 2010 987 CYCLIN D2 AND COMPENSATORY ␤-CELL HYPERPLASIA TABLE 1 Body weight and blood glucose of mice A 12 * Nonfasted Body blood 10 * * Weight P vs. glucose P vs. 8 (g) control (mg/dl) control 6 10–12 weeks of age 4 * Control 24.8 Ϯ 1.5 149 Ϯ 9 2 LIRKO 24.2 Ϯ 1.7 NS 198 Ϯ 40 NS D2KO/LIRKO 18.5 Ϯ 1.4 Ͻ0.01 Ͼ600 Ͻ0.000,001 Plasma Insulin (ng/ml) 0 control LIRKO D2KO D2KO D2KO 19.7 Ϯ 1.4 0.024 188 Ϯ 22 0.042 25 weeks of age /LIRKO Control 23.1 Ϯ 0.9 172 Ϯ 5 IRS1KO 18.4 Ϯ 1.1 0.012 176 Ϯ 9NS B D2KO/IRS1KO 13.5 Ϯ 0.4 Ͻ0.005 390 Ϯ 41 Ͻ0.005 200 * D2KO 21.2 Ϯ 0.8 NS 253 Ϯ 18 Ͻ0.005 Data are means Ϯ SE (n ϭ 5–9 male mice). NS, nonsignificant. 150 * * 100 RESEARCH DESIGN AND METHODS Animal breeding and genotyping. All studies and procedures were per- formed after approval according to the institutional animal committee regu- 50 lations in both institutions. The creation and characterization of the LIRKO, IRS1KO, and D2KO mice has previously been described (20–22,24). All mice 0 were maintained on a 12-h light/12-h dark cycle with ad libitum access to Plasma Glucagon (pg/ml) controlLIRKO D2KO D2KO water and food, and a mixed mating scheme was adopted for breeding. In the /LIRKO first group, males and females homozygous for loxP sites (IRLox) and expressing Cre recombinase on an albumin promoter were bred with mice control D2KO/LIRKO lacking cyclin D2. In the second group, males and females carrying either the C insulin receptor substrate 1 or cyclin D2 alleles were used. In the D2KO/LIRKO LIRKO D2KO study, the breeding generated mice homozygous for loxP (controls), LIRKO, 600 * * D2KO/LIRKO, and D2KO, and in the D2KO/IRS1KO study the genotypes * included IRS1KO (cycD2ϩ/Ϫ;irs1Ϫ/Ϫ), D2KO/IRS1KO (cycD2Ϫ/Ϫ;irs1Ϫ/Ϫ), 500 Ϫ/Ϫ ϩ/Ϫ ϩ/Ϫ ϩ/Ϫ * D2KO (cycD2 ;irs1 ), and their controls (cycD2 ;irs1 ). DNA ex- 400 * tracted from tails was used for PCR-based genotyping (13,22). All studies * * included animals from a mixed genetic background. Pancreata were collected 300 * for immunohistochemical analyses (25), and islets were isolated using previ- * 200 * ously described methods (26). * * Glucose and insulin tolerance tests and plasma insulin levels. Following 100 a 16-h fast, baseline blood glucose levels were measured from tail-vein samples using a glucometer (LifeScan, Milpitas, CA). Glucose tolerance (mg/dl) Blood Glucose 0 tests were performed (25) in 7-week-old (D2KO/LIRKO) or 25-week-old 0 15 30 60 120 (D2KO/IRS1KO) mice. Plasma insulin levels were measured by ELISA Minutes after IP glucose injection (Linco Research). Insulin tolerance tests were performed on 25-week-old mice (25). FIG. 1. D2KO/LIRKO mice exhibit severe hyperglycemia and early Real-time RT–quantitative PCR. Quantitative real-time RT-PCR was per- diabetes. A and B: Plasma insulin (A) and glucagon (B) levels were formed on total RNA samples extracted from islets (RNeasy Mini Kit; Qiagen, measured at random fed states in control (white), LIRKO (light gray), > P* .(10–4 ؍ Valencia, CA). cDNA samples were amplified by using the SYBR Green PCR D2KO/LIRKO (black), and D2KO (dark gray) mice (n Master Mix (Applied Biosystems) and analyzed on an ABI PRISM 7900 0.05 as indicated by bars. C: Glucose tolerance tests were performed in sequence detection system (Applied Biosystems). All primer sequences are 7-week-old mice, and blood glucose was measured at 0, 15, 30, 60, and 120 min after intraperitoneal (IP) injection of glucose (2 g/kg body .8–4 ؍ available in the online appendix, available at http://diabetes.diabetesjournals.
Load more

Recommended publications
  • Cyclin D2 Activates Cdk2 in Preference to Cdk4 in Human Breast Epithelial Cells
    Oncogene (1997) 14, 1329 ± 1340 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Cyclin D2 activates Cdk2 in preference to Cdk4 in human breast epithelial cells Kimberley J Sweeney, Boris Sarcevic, Robert L Sutherland and Elizabeth A Musgrove Cancer Research Program, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, NSW 2010, Australia To investigate the possibility of diering roles for cyclins Similarly, overexpression of cyclin D2 in myeloid cells D1 and D2 in breast epithelial cells, we examined the results in a decrease in the duration of G1 and an expression, cell cycle regulation and activity of these two increase in the percentage of cells in S-phase (Ando et G1 cyclins in both 184 normal breast epithelial cells and al., 1993; Kato and Sherr, 1993). Microinjection or T-47D breast cancer cells. Synchronisation studies in 184 electroporation of cyclin D1 or cyclin D2 antibodies cells demonstrated that cyclin D1 and cyclin D2 were demonstrated that these proteins were not only rate- dierentially regulated during G1, with cyclin D2 limiting but essential for progress through G1 (Baldin abundance increasing by 3.7-fold but only small changes et al., 1993; Quelle et al., 1993; Lukas et al., 1995b). in cyclin D1 abundance observed. The functional These eects are thought to be mediated by activation consequences of increased cyclin D2 expression were of cyclin-dependent kinases (CDKs) and consequent examined in T-47D cells, which express no detectable phosphorylation of the product of the retinoblastoma cyclin D2. Induced expression of cyclin D2 resulted in susceptibility gene, pRB (Hunter and Pines, 1994; increases in cyclin E expression, pRB phosphorylation Sherr, 1994).
    [Show full text]
  • P27 and P21 Collaborate in the Regulation of Transcription By
    6860–6873 Nucleic Acids Research, 2015, Vol. 43, No. 14 Published online 13 June 2015 doi: 10.1093/nar/gkv593 p27Kip1 and p21Cip1 collaborate in the regulation of transcription by recruiting cyclin–Cdk complexes on the promoters of target genes Serena Orlando1, Edurne Gallastegui1, Arnaud Besson2,3,4, Gabriel Abril1, Rosa Aligue´ 1, Maria Jesus Pujol1 and Oriol Bachs1,* 1Department of Cell Biology, Immunology and Neurosciences, University of Barcelona, 08036-Barcelona, Spain, 2INSERM UMR1037, Cancer Research Center of Toulouse, Toulouse, France, 3Universite´ de Toulouse, Toulouse, France and 4CNRS ERL5294, Toulouse, France Received December 22, 2014; Revised May 20, 2015; Accepted May 23, 2015 ABSTRACT through Cdk20 (2). Many members of this family, includ- ing Cdk4, Cdk6, Cdk2 and Cdk1, are involved in cell-cycle Transcriptional repressor complexes containing regulation (3). Cdk4, Cdk6 and Cdk2 regulate progression p130 and E2F4 regulate the expression of genes in- through the G1 phase although additionally, Cdk2 also reg- volved in DNA replication. During the G1 phase of ulates S phase. Finally, Cdk1 regulates mitosis. Binding the cell cycle, sequential phosphorylation of p130 of Cdks to specific cyclins confers a functional specializa- by cyclin-dependent kinases (Cdks) disrupts these tion to each complex (3). In response to mitogenic stim- complexes allowing gene expression. The Cdk in- uli, the synthesis of the D-type cyclins is induced in early– Kip1 hibitor and tumor suppressor p27 associates with mid G1 phase. These cyclins associate with Cdk4 and Cdk6, p130 and E2F4 by its carboxyl domain on the pro- forming complexes that phosphorylate and inactivate mem- moters of target genes but its role in the regulation bers of the retinoblastoma family of pocket proteins (pRb, of transcription remains unclear.
    [Show full text]
  • Requirement for Cyclin D3 in Germinal Center Formation and Function
    Cell Research (2010) :1-16. © 2010 IBCB, SIBS, CAS All rights reserved 1001-0602/10 $ 32.00 npg ORIGINAL ARTICLE www.nature.com/cr Requirement for cyclin D3 in germinal center formation and function Jonathan U Peled1, J Jessica Yu1, Jeganathan Venkatesh2, Enguang Bi1, B Belinda Ding1, 5, Melissa Krupski-Downs1, Rita Shaknovich3, Piotr Sicinski4, Betty Diamond2, Matthew D Scharff1, B Hilda Ye1 1Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA; 2The Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA; 3Depart- ments of Medicine and Pathology, Weill Cornell College of Medicine, New York, NY 10021, USA; 4Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Pathology, Harvard Medical School, Boston, MA 02115, USA Germinal centers (GC) of secondary lymphoid tissues are critical to mounting a high-affinity humoral immune response. B cells within the GC undergo rapid clonal expansion and selection while diversifying their antibody genes. Although it is generally believed that GC B cells employ a unique proliferative program to accommodate these pro- cesses, little is known about how the GC-associated cell cycle is orchestrated. The D-type cyclins constitute an im- portant component of the cell cycle engine that enables the cells to respond to physiological changes. Cell type- and developmental stage-specific roles of D-type cyclins have been described but the cyclin D requirement during GC reaction has not been addressed. In this study, we report that cyclin D3 is largely dispensable for proliferation and Ig class switching of in vitro activated B cells.
    [Show full text]
  • Altered Gene Expression Encoding Cytochines, Grow Factors and Cell Cycle Regulators in the Endometrium of Women with Chronic Endometritis
    diagnostics Article Altered Gene Expression Encoding Cytochines, Grow Factors and Cell Cycle Regulators in the Endometrium of Women with Chronic Endometritis Ettore Cicinelli 1, Amerigo Vitagliano 2,* , Vera Loizzi 1, Dominique De Ziegler 3, Margherita Fanelli 4 , Stefano Bettocchi 1, Claudia Nardelli 1, Giuseppe Trojano 1, Rossana Cicinelli 1, Crescenzio Francesco Minervini 5 , Daniela Leronni 6 and Luigi Viggiano 7 1 2nd Unit of Obstetrics and Gynecology, Department of Biomedical and Human Oncologic Science, Policlinico University of Bari, 70124 Bari, Italy; [email protected] (E.C.); [email protected] (V.L.); [email protected] (S.B.); [email protected] (C.N.); [email protected] (G.T.); [email protected] (R.C.) 2 Department of Women and Children’s Health, University of Padua, 35128 Padua, Italy 3 Department of Ob Gyn and Reproductive Medicine, Foch Hospital, 92150 Suresnes, France; [email protected] 4 Interdisciplinary Department of Medicine, University of Bari, 70124 Bari, Italy; [email protected] 5 Department of Emergency and Organ Transplantation (D.E.T.O.), Hematology Section, University of Bari, 70124 Bari, Italy; [email protected] 6 Neuroapoptosis Laboratory, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; [email protected] 7 Department of Biology, University of Bari, 700124 Bari, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-333-1467105; Fax: +39-049-8211785 Citation: Cicinelli, E.; Vitagliano, A.; Loizzi, V.; De Ziegler, D.; Fanelli, M.; Abstract: To evaluate the expression of genes encoding cytokines, grow factors and cell cycle regula- Bettocchi, S.; Nardelli, C.; Trojano, G.; tors in the proliferative endometrium of women with chronic endometritis (CE) compared to controls.
    [Show full text]
  • Increased Expression of Unmethylated CDKN2D by 5-Aza-2'-Deoxycytidine in Human Lung Cancer Cells
    Oncogene (2001) 20, 7787 ± 7796 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc Increased expression of unmethylated CDKN2D by 5-aza-2'-deoxycytidine in human lung cancer cells Wei-Guo Zhu1, Zunyan Dai2,3, Haiming Ding1, Kanur Srinivasan1, Julia Hall3, Wenrui Duan1, Miguel A Villalona-Calero1, Christoph Plass3 and Gregory A Otterson*,1 1Division of Hematology/Oncology, Department of Internal Medicine, The Ohio State University-Comprehensive Cancer Center, Columbus, Ohio, OH 43210, USA; 2Department of Pathology, The Ohio State University-Comprehensive Cancer Center, Columbus, Ohio, OH 43210, USA; 3Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University-Comprehensive Cancer Center, Columbus, Ohio, OH 43210, USA DNA hypermethylation of CpG islands in the promoter Introduction region of genes is associated with transcriptional silencing. Treatment with hypo-methylating agents can Methylation of cytosine residues in CpG sequences is a lead to expression of these silenced genes. However, DNA modi®cation that plays a role in normal whether inhibition of DNA methylation in¯uences the mammalian development (Costello and Plass, 2001; expression of unmethylated genes has not been exten- Li et al., 1992), imprinting (Li et al., 1993) and X sively studied. We analysed the methylation status of chromosome inactivation (Pfeifer et al., 1990). To date, CDKN2A and CDKN2D in human lung cancer cell lines four mammalian DNA methyltransferases (DNMT) and demonstrated that the CDKN2A CpG island is have been identi®ed (Bird and Wole, 1999). Disrup- methylated, whereas CDKN2D is unmethylated. Treat- tion of the balance in methylated DNA is a common ment of cells with 5-aza-2'-deoxycytidine (5-Aza-CdR), alteration in cancer (Costello et al., 2000; Costello and an inhibitor of DNA methyltransferase 1, induced a dose Plass, 2001; Issa et al., 1993; Robertson et al., 1999).
    [Show full text]
  • Cyclin-Dependent Kinases and CDK Inhibitors in Virus-Associated Cancers Shaian Tavakolian, Hossein Goudarzi and Ebrahim Faghihloo*
    Tavakolian et al. Infectious Agents and Cancer (2020) 15:27 https://doi.org/10.1186/s13027-020-00295-7 REVIEW Open Access Cyclin-dependent kinases and CDK inhibitors in virus-associated cancers Shaian Tavakolian, Hossein Goudarzi and Ebrahim Faghihloo* Abstract The role of several risk factors, such as pollution, consumption of alcohol, age, sex and obesity in cancer progression is undeniable. Human malignancies are mainly characterized by deregulation of cyclin-dependent kinases (CDK) and cyclin inhibitor kinases (CIK) activities. Viruses express some onco-proteins which could interfere with CDK and CIKs function, and induce some signals to replicate their genome into host’scells.By reviewing some studies about the function of CDK and CIKs in cells infected with oncoviruses, such as HPV, HTLV, HERV, EBV, KSHV, HBV and HCV, we reviewed the mechanisms of different onco-proteins which could deregulate the cell cycle proteins. Keywords: CDK, CIKs, Cancer, Virus Introduction the key role of the phosphorylation in the entrance of Cell division is controlled by various elements [1–10], the cells to the S phase of the cell cycle [19]. especially serine/ threonine protein kinase complexes, CDK genes are classified in mammalian cells into differ- called cyclin-dependent kinases (CDKs), and cyclins, ent classes of CDKs, especially some important regulatory whose expression is prominently regulated by the bind- ones (The regulatory CDKs play important roles in medi- ing to CDK inhibitors [11, 12]. In all eukaryotic species, ating cell cycle). Each of these CDKs could interact with a these genes are classified into different families. It is specific cyclin and thereby regulating the expression of well-established that the complexes of cyclin and CDK different genes [20, 21].
    [Show full text]
  • Open Data for Differential Network Analysis in Glioma
    International Journal of Molecular Sciences Article Open Data for Differential Network Analysis in Glioma , Claire Jean-Quartier * y , Fleur Jeanquartier y and Andreas Holzinger Holzinger Group HCI-KDD, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Auenbruggerplatz 2/V, 8036 Graz, Austria; [email protected] (F.J.); [email protected] (A.H.) * Correspondence: [email protected] These authors contributed equally to this work. y Received: 27 October 2019; Accepted: 3 January 2020; Published: 15 January 2020 Abstract: The complexity of cancer diseases demands bioinformatic techniques and translational research based on big data and personalized medicine. Open data enables researchers to accelerate cancer studies, save resources and foster collaboration. Several tools and programming approaches are available for analyzing data, including annotation, clustering, comparison and extrapolation, merging, enrichment, functional association and statistics. We exploit openly available data via cancer gene expression analysis, we apply refinement as well as enrichment analysis via gene ontology and conclude with graph-based visualization of involved protein interaction networks as a basis for signaling. The different databases allowed for the construction of huge networks or specified ones consisting of high-confidence interactions only. Several genes associated to glioma were isolated via a network analysis from top hub nodes as well as from an outlier analysis. The latter approach highlights a mitogen-activated protein kinase next to a member of histondeacetylases and a protein phosphatase as genes uncommonly associated with glioma. Cluster analysis from top hub nodes lists several identified glioma-associated gene products to function within protein complexes, including epidermal growth factors as well as cell cycle proteins or RAS proto-oncogenes.
    [Show full text]
  • Up-Regulation of Cyclin-Dependent Kinase 4/Cyclin D2 Expression but Down- Regulation of Cyclin-Dependent Kinase 2/Cyclin E in Testicular Germ Cell Tumors1
    [CANCER RESEARCH 61, 4214–4221, May 15, 2001] Up-Regulation of Cyclin-dependent Kinase 4/Cyclin D2 Expression but Down- Regulation of Cyclin-dependent Kinase 2/Cyclin E in Testicular Germ Cell Tumors1 Bettina A. Schmidt,2 Achim Rose, Christine Steinhoff, T. Strohmeyer, Michael Hartmann, and Rolf Ackermann Department of Urology, Heinrich-Heine-University of Duesseldorf, 40225 Duesseldorf, Germany [B. A. S., A. R., C. S., R. A.], and Department of Urology, Hospital of the Armed Forces, 22099 Hamburg, Germany [M. H.] ABSTRACT causes death in about 20–30% of patients with highly advanced stages. The present state of research provides only marginal insights Testicular germ cell tumors (GCT) characteristically display two chro- into the molecular pathogenesis of these tumors and the mechanisms mosome 12 abnormalities: the isochromosome i(12p) and concomitant underlying the effectiveness of chemotherapy. deletions of the long arm. Some genes important in the control of the G -S 1 The most frequent cytogenetic observation indicative of testicular cell cycle checkpoint G1-S, i.e., cyclin-dependent kinases 2 and 4, cyclin D2 are located on this chromosomal region. Therefore, testicular GCTs were GCT is the presence of an isochromosome of the short arm of analyzed as to the expression of CDK2, CDK4, CDK6, and the expression chromosome 12, i12(p), in up to 80% of all tumors. Although this of their catalytic partners cyclins D1, D2 and E by semiquantitative finding has been confirmed by various investigators (6–8), its diag- reverse transcription-PCR. Cyclin D2, located on 12p, was overexpressed nostic and prognostic relevance is still under discussion (9, 10).
    [Show full text]
  • Autoimmunity in a Mouse Model of Lupus Deficiency Promotes B1a
    Cyclin-Dependent Kinase Inhibitor Cdkn2c Deficiency Promotes B1a Cell Expansion and Autoimmunity in a Mouse Model of Lupus This information is current as Hari-Hara S. K. Potula, Zhiwei Xu, Leilani Zeumer, Allison of September 25, 2021. Sang, Byron P. Croker and Laurence Morel J Immunol 2012; 189:2931-2940; Prepublished online 15 August 2012; doi: 10.4049/jimmunol.1200556 http://www.jimmunol.org/content/189/6/2931 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2012/08/15/jimmunol.120055 Material 6.DC1 http://www.jimmunol.org/ References This article cites 42 articles, 14 of which you can access for free at: http://www.jimmunol.org/content/189/6/2931.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Cyclin-Dependent Kinase Inhibitor Cdkn2c Deficiency Promotes B1a Cell Expansion and Autoimmunity in a Mouse Model of Lupus Hari-Hara S.
    [Show full text]
  • Inactivation of Cyclin D2 Gene in Prostate Cancers by Aberrant Promoter Methylation
    4730 Vol. 9, 4730–4734, October 15, 2003 Clinical Cancer Research Inactivation of Cyclin D2 Gene in Prostate Cancers by Aberrant Promoter Methylation Asha Padar, Ubaradka G. Sathyanarayana, from our laboratory (R. Maruyama et al., Clin. Cancer Res., Makoto Suzuki, Riichiroh Maruyama, 8: 514–519, 2002)] studied in the same set of samples. The concordances between methylation of Cyclin D2 and the Jer-Tsong Hsieh, Eugene P. Frenkel, ␤ 1 methylation of RAR , GSTP1, CDH13, RASSF1A, and APC John D. Minna, and Adi F. Gazdar were statistically significant, whereas methylation of P16, Hamon Center for Therapeutic Oncology Research [A. P., U. G. S., DAPK, FHIT, and CDH1 were not significant. The differ- M. S., R. M., J. D. M., A. F. G.], The Simmons Cancer Center ences in methylation index between malignant and nonma- [E. P. F.], and Departments of Pathology [U. G. S., A. F. G.], Urology [J-T. H.], Internal Medicine [J. D. M.], and Pharmacology [J. D. M.], lignant tissues for all 10 genes were statistically significant The University of Texas Southwestern Medical Center, Dallas, (P < 0.0001). Among clinicopathological correlations, the Texas 75390 high Gleason score group had significantly greater methyl- Although the .(0.004 ؍ ation frequency of Cyclin D2 (42%; P high preoperative serum prostate-specific antigen (PSA) ABSTRACT group did not have significantly greater methylation fre- Purpose: Loss or abnormal expression of Cyclin D2,a quency, methylation of Cyclin D2 had higher mean PSA crucial cell cycle-regulatory gene, has been described in value. Also, the prostate cancers in the high Gleason score human cancers; however, data for prostate tumors are lack- group had high mean values of PSA.
    [Show full text]
  • Selective Usage of D-Type Cyclins in Lymphoid Malignancies
    Leukemia (1999) 13, 1335–1342 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu Selective usage of D-type cyclins in lymphoid malignancies R Suzuki1,2, H Kuroda1, H Komatsu1, Y Hosokawa1, Y Kagami2, M Ogura2, S Nakamura3, Y Kodera4, Y Morishima2, R Ueda5 and M Seto1 1Laboratory of Chemotherapy, 2Department of Hematology and Chemotherapy, and 3Department of Pathology and Clinical Laboratories, Aichi Cancer Center; 4Department of Internal Medicine, Japanese Red Cross Nagoya First Hospital; and 5Second Department of Internal Medicine, Nagoya City University School of Medicine, Nagoya, Japan Three D-type cyclins, cyclin D1, D2 and D3, belong to the G1 some 14,11–13 in much the same way as the c-myc gene is cyclin, which regulates the G1/S transition of the cell cycle, and affected by t(8;14) translocations in Burkitt’s lymphoma14 and feature highly homologous amino acid sequences. The cyclin the BCL-2 gene by t(14;18) translocations in follicular lym- D1 gene was found to be transcriptionally activated in B-lymph- 15 oid malignancies with t(11;14), but available information is lim- phomas. The breakpoints occur at variable distances from ited regarding expression of cyclin D2 and D3 in hematopoietic the cyclin D1 gene, typically up to 120 kb, but the net effect malignancies. We examined the expressions of three D-type appears to be the transcriptional activation of cyclin cyclins to investigate how these homologous genes are differ- D1.12,13,16–18 Several groups including ours have reported entially used.
    [Show full text]
  • Cdkn2a, the Cyclin-Dependent Kinase Inhibitor Encoding P16ink4a and P19arf, Is a Candidate for the Plasmacytoma Susceptibility Locus, Pctr1
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 2429–2434, March 1998 Genetics Cdkn2a, the cyclin-dependent kinase inhibitor encoding p16INK4a and p19ARF, is a candidate for the plasmacytoma susceptibility locus, Pctr1 SHULING ZHANG,EDWARD S. RAMSAY, AND BEVERLY A. MOCK* Laboratory of Genetics, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255 Communicated by Michael Potter, National Institutes of Health, Bethesda, MD, December 24, 1997 (received for review November 17, 1997) ABSTRACT Plasma cell tumor induction in mice by cytoma susceptibilityyresistance locus resides. The protein pristane is under multigenic control. BALByc mice are sus- products of these genes bind to the CDKs CDK4 and CDK6 (6, ceptible to tumor development; whereas DBAy2 mice are 7), which, in turn, form complexes with the D-type G1 cyclins resistant. Restriction fragment length polymorphisms be- that phosphorylate pRb to control both cell cycle and tumor tween BALByc and DBAy2 for Cdkn2a(p16) and Cdkn2b(p15), suppression (8, 9). We compared the sequences of p16 and p18 and between BALByc and Mus spretus for Cdkn2c(p18INK4c) between susceptible (BALByc) and resistant (DBAy2N) were used to position these loci with respect to the Pctr1 locus. strains of mice, and found sequence variants in p16 located in These cyclin-dependent kinase (CDK) inhibitors mapped to a two different ankyrin repeat regions of the gene. DBAy2 (wild 6 cM interval of chromosome 4 between Ifna and Tal1. type) and BALByc A134C and G232A variants of the p16 C.D2-Chr 4 congenic strains harboring DBAy2 alleles asso- genes were fused to the glutathione S-transferase (GST) gene, ciated with the Pctr1 locus contained DBAy2 ‘‘resistant’’ and purified GST fusion proteins were tested for their ability alleles of the CDK4yCDK6 inhibitors p16 and p15.
    [Show full text]