Mammalian Cell-Cycle Regulation: Several Cdks, Numerous Cyclins and Diverse Compensatory Mechanisms
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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). -
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. -
Original Article Expression of Cell-Cycle Regulators Is Associated with Invasive Behavior and Poor Prognosis in Prolactinomas
Int J Clin Exp Pathol 2016;9(3):3245-3255 www.ijcep.com /ISSN:1936-2625/IJCEP0021009 Original Article Expression of cell-cycle regulators is associated with invasive behavior and poor prognosis in prolactinomas Chunhui Liu1,2*, Weiyan Xie1,2*, Dan Wu3, Zhenye Li2, Chuzhong Li1,2, Yazhuo Zhang1,2 1Beijing Neurosurgical Institute, Capital Medical University, Beijing, China; 2Beijing Tiantan Hospital, Capital Medical University, Beijing, China; 3Department of Neurology, Beijing Renhe Hospital, Beijing, China. *Equal con- tributors. Received December 2, 2015; Accepted February 13, 2016; Epub March 1, 2016; Published March 15, 2016 Abstract: Prolactinomas are the most common pituitary tumors. The mechanisms of cell-cycle regulators underlying their invasive biological behavior and poor prognosis have not yet been fully clarified. We classified 48 human pro- lactinomas as invasive or non-invasive and determined cyclin D1, cyclin E1, p16, p27, Cdk2 and Cdk4 expression by immunohistochemistry analysis of tissue microarray constructs. Then we determined the diagnostic and prognostic value of the cell-cycle regulators expression in human prolactinomas. In this proof of principle study we found that nuclear p16 and p27 expression levels were much lower in invasive prolactinomas compared with non-invasive prolactinomas. Meanwhile, significantly higher cyclin D1 and cyclin E1 expression in invasive prolactinomas com- pared with normal pituitary or non-invasive prolactinomas. No difference was found in Cdk2 or Cdk4 protein levels in invasive or non-invasive prolactinomas. Regarding clinical outcome, the expression ratios of cyclin D1/p16 and cyclin E1/p27 were significantly positively correlated with clinically inferior outcome (P<0.001), while Cdk2 or Cdk4 expression showed no relationship with clinical outcome. -
Cell Cycle Arrest and DNA Endoreduplication Following P21waf1/Cip1 Expression
Oncogene (1998) 17, 1691 ± 1703 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression Stewart Bates, Kevin M Ryan, Andrew C Phillips and Karen H Vousden ABL Basic Research Program, NCI-FCRDC, Building 560, Room 22-96, West 7th Street, Frederick, Maryland 21702-1201, USA p21Waf1/Cip1 is a major transcriptional target of p53 and there are an increasing number of regulatory mechan- has been shown to be one of the principal mediators of isms that serve to inhibit cdk activity. Primary amongst the p53 induced G1 cell cycle arrest. We show that in these is the expression of cdk inhibitors (CDKIs) that addition to the G1 block, p21Waf1/Cip1 can also contribute can bind to and inhibit cyclin/cdk complexes (Sherr to a delay in G2 and expression of p21Waf1/Cip1 gives rise and Roberts, 1996). These fall into two classes, the to cell cycle pro®les essentially indistinguishable from INK family which bind to cdk4 and cdk6 and inhibit those obtained following p53 expression. Arrest of cells complex formation with D-cyclins, and the p21Waf1/Cip1 in G2 likely re¯ects an inability to induce cyclin B1/cdc2 family that bind to cyclin/cdk complexes and inhibit kinase activity in the presence of p21Waf1/Cip1, although the kinase activity. inecient association of p21Waf1/Cip1 and cyclin B1 The p21Waf1/Cip1 family of CDKIs include p21Waf1/Cip1, suggests that the mechanism of inhibition is indirect. p27 and p57 and are broad range inhibitors of cyclin/ Cells released from an S-phase block were not retarded cdk complexes (Gu et al., 1993; Harper et al., 1993; in their ability to progress through S-phase by the Xiong et al., 1993; Firpo et al., 1994; Polyak et al., presence of p21Waf1/Cip1, despite ecient inhibition of 1994; Toyoshima and Hunter, 1994; Lee et al., 1995; cyclin E, A and B1 dependent kinase activity, suggesting Matsuoka et al., 1995). -
CDK1/Cyclin A2, Active (C0244)
CDK1/Cyclin A2, active, GST-tagged, human PRECISIOÒ Kinase recombinant, expressed in Sf9 cells Catalog Number C0244 Storage Temperature –70 °C Synonyms: Figure 1. CDK1: CDC2, CDC28A, DKFZp686L20222, SDS-PAGE Gel of Typical Lot: MGC111195 ³70% (SDS-PAGE, densitometry) Cyclin A2: CCN1, CCNA 170 130 Product Description 95 Cyclin A2 CDK1 or Cell Division Control protein 1 is essential for 72 the completion of START, the controlling event in the 56 CDK1 cell cycle that is required to initiate mitosis. CDK1 is a 43 catalytic subunit of a protein kinase complex, called the M-Phase Promoting Factor that induces entry into 34 mitosis and is universal among eukaryotes.1 Phosphorylation of Bcl-2 in G2/M phase-arrested cells following photodynamic therapy with hypericin involves Figure 2. a CDK1-mediated signal and delays the onset of Specific Activity of Typical Lot: apoptosis. Therapeutic potential of the CDK inhibitor, 151–205 nmole/min/mg NU2058, in androgen-independent prostate cancer has also been demonstrated.2 520,000 This recombinant product was expressed by 390,000 baculovirus in Sf9 insect cells using an N-terminal cpm) GST-tag. The gene accession numbers are NM 001786 260,000 and NM 001237. It is supplied in 50 mM Tris-HCl, 130,000 pH 7.5, with 150 mM NaCl, 0.25 mM DTT, 0.1 mM Activity ( EGTA, 0.1 mM EDTA, 0.1 mM PMSF, and 25% 0 glycerol. 0 40 80 120 160 Protein (ng) Molecular mass: CDK1 ~59 kDa Procedure Cyclin A2 ~78 kDa Preparation Instructions Kinase Assay Buffer – 25 mM MOPS, pH 7.2, 12.5 mM Precautions and Disclaimer glycerol 2-phosphate, 25 mM MgCl2, 5 mM EGTA, and This product is for R&D use only, not for drug, 2 mM EDTA. -
Mitosis Vs. Meiosis
Mitosis vs. Meiosis In order for organisms to continue growing and/or replace cells that are dead or beyond repair, cells must replicate, or make identical copies of themselves. In order to do this and maintain the proper number of chromosomes, the cells of eukaryotes must undergo mitosis to divide up their DNA. The dividing of the DNA ensures that both the “old” cell (parent cell) and the “new” cells (daughter cells) have the same genetic makeup and both will be diploid, or containing the same number of chromosomes as the parent cell. For reproduction of an organism to occur, the original parent cell will undergo Meiosis to create 4 new daughter cells with a slightly different genetic makeup in order to ensure genetic diversity when fertilization occurs. The four daughter cells will be haploid, or containing half the number of chromosomes as the parent cell. The difference between the two processes is that mitosis occurs in non-reproductive cells, or somatic cells, and meiosis occurs in the cells that participate in sexual reproduction, or germ cells. The Somatic Cell Cycle (Mitosis) The somatic cell cycle consists of 3 phases: interphase, m phase, and cytokinesis. 1. Interphase: Interphase is considered the non-dividing phase of the cell cycle. It is not a part of the actual process of mitosis, but it readies the cell for mitosis. It is made up of 3 sub-phases: • G1 Phase: In G1, the cell is growing. In most organisms, the majority of the cell’s life span is spent in G1. • S Phase: In each human somatic cell, there are 23 pairs of chromosomes; one chromosome comes from the mother and one comes from the father. -
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. -
The Expression of P21/WAF-1 and Cyclin B1 Mediate Mitotic Delay in X-Irradiated Fibroblasts
ANTICANCER RESEARCH 25: 1123-1130 (2005) The Expression of p21/WAF-1 and Cyclin B1 Mediate Mitotic Delay in x-Irradiated Fibroblasts MICKAEL J. CARIVEAU1,2, CHARLES J. KOVACS2, RON R. ALLISON2, ROBERTA M. JOHNKE2, GERHARD W. KALMUS3 and MARK EVANS2 1Department of Physics, East Carolina University, Greenville NC, 27858; 2Department of Radiation Oncology, The Brody School of Medicine, East Carolina University, Greenville NC, 27858; 3Department of Biology, East Carolina University, Greenville NC, 27858, U.S.A. Abstract. Background: To better understand the relationship Initiation and maintenance of cell cycle arrest is regulated between mitotic delay and the disruption of cyclin B1 and p21 in by a group of proteins known as the cyclins which function x-irradiated fibroblasts, studies were carried out to establish by coupling to their corresponding cyclin dependent kinases correlations between the downregulation of cyclin B1 by the cyclin (CDK) (6-9). Of particular interest to cell cycle arrest in kinase inhibitor (CKI) p21 and the induction of mitotic delay in response to DNA damage is the G2/M damage checkpoint the NIH3T3 fibroblast. Materials and Methods: Cell cycle kinetics which is regulated by cyclin B1/CDK1 and initiated by DNA were used to analyze mitotic delay in irradiated NIH3T3 cells and damage activation of the cyclin kinase inhibitor p21(10-14). immunocytochemistry incorporated to assess the expression of The inhibitory potential of p21 is well established; however, cyclin B1 and p21, following 2 or 4Gy x-irradiation. Results and there is still much confusion about the role of p21 in the Discussion: Results indicate a dose dependent increase in mitotic irradiated cell (15, 16). -
Nerve Growth Factor Induces Transcription of the P21 WAF1/CIP1 and Cyclin D1 Genes in PC12 Cells by Activating the Sp1 Transcription Factor
The Journal of Neuroscience, August 15, 1997, 17(16):6122–6132 Nerve Growth Factor Induces Transcription of the p21 WAF1/CIP1 and Cyclin D1 Genes in PC12 Cells by Activating the Sp1 Transcription Factor Guo-Zai Yan and Edward B. Ziff Howard Hughes Medical Institute, Department of Biochemistry, Kaplan Cancer Center, New York University Medical Center, New York, New York 10016 The PC12 pheochromocytoma cell line responds to nerve in which the Gal4 DNA binding domain is fused to the Sp1 growth factor (NGF) by gradually exiting from the cell cycle and transactivation domain, indicating that this transactivation do- differentiating to a sympathetic neuronal phenotype. We have main is regulated by NGF. Epidermal growth factor, which is a shown previously (Yan and Ziff, 1995) that NGF induces the weak mitogen for PC12, failed to induce any of these promoter expression of the p21 WAF1/CIP1/Sdi1 (p21) cyclin-dependent constructs. We consider a model in which the PC12 cell cycle kinase (Cdk) inhibitor protein and the G1 phase cyclin, cyclin is arrested as p21 accumulates and attains inhibitory levels D1. In this report, we show that induction is at the level of relative to Cdk/cyclin complexes. Sustained activation of p21 transcription and that the DNA elements in both promoters that expression is proposed to be a distinguishing feature of the are required for NGF-specific induction are clusters of binding activity of NGF that contributes to PC12 growth arrest during sites for the Sp1 transcription factor. NGF also induced a differentiation synthetic -
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. -
Insight Into Bortezomib Focusing on Its Efficacy Against P-Gp-Positive
International Journal of Molecular Sciences Article Insight into Bortezomib Focusing on Its Efficacy against P-gp-Positive MDR Leukemia Cells Tomáš Kyca 1, Lucia Pavlíková 1,2, Viera Boháˇcová 1, Anton Mišák 3 , Alexandra Poturnayová 1, Albert Breier 1,4,* , Zdena Sulová 1,* and Mário Šereš 1,2,* 1 Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 84505 Bratislava, Slovakia; [email protected] (T.K.); [email protected] (L.P.); [email protected] (V.B.); [email protected] (A.P.) 2 Institute of Zoology, Slovak Academy of Sciences, Dúbravská cesta 9, 84506 Bratislava, Slovakia 3 Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 84505 Bratislava, Slovakia; [email protected] 4 Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237 Bratislava 1, Slovakia * Correspondence: [email protected] (A.B.); [email protected] (Z.S.); [email protected] (M.Š.); Tel.: +421-2-593-25-514 or +421-918-674-514 (A.B.); +421-2-3229-5510 (Z.S.) Abstract: In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. -
Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase
cells Review Role of Cyclin-Dependent Kinase 1 in Translational Regulation in the M-Phase Jaroslav Kalous *, Denisa Jansová and Andrej Šušor Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic, Rumburska 89, 27721 Libechov, Czech Republic; [email protected] (D.J.); [email protected] (A.Š.) * Correspondence: [email protected] Received: 28 April 2020; Accepted: 24 June 2020; Published: 27 June 2020 Abstract: Cyclin dependent kinase 1 (CDK1) has been primarily identified as a key cell cycle regulator in both mitosis and meiosis. Recently, an extramitotic function of CDK1 emerged when evidence was found that CDK1 is involved in many cellular events that are essential for cell proliferation and survival. In this review we summarize the involvement of CDK1 in the initiation and elongation steps of protein synthesis in the cell. During its activation, CDK1 influences the initiation of protein synthesis, promotes the activity of specific translational initiation factors and affects the functioning of a subset of elongation factors. Our review provides insights into gene expression regulation during the transcriptionally silent M-phase and describes quantitative and qualitative translational changes based on the extramitotic role of the cell cycle master regulator CDK1 to optimize temporal synthesis of proteins to sustain the division-related processes: mitosis and cytokinesis. Keywords: CDK1; 4E-BP1; mTOR; mRNA; translation; M-phase 1. Introduction 1.1. Cyclin Dependent Kinase 1 (CDK1) Is a Subunit of the M Phase-Promoting Factor (MPF) CDK1, a serine/threonine kinase, is a catalytic subunit of the M phase-promoting factor (MPF) complex which is essential for cell cycle control during the G1-S and G2-M phase transitions of eukaryotic cells.