DOCSLIB.ORG

Checkpoint Control and Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Checkpoint Control and Cancer Oncogene (2012) 31, 2601–2613 & 2012 Macmillan Publishers Limited All rights reserved 0950-9232/12 www.nature.com/onc REVIEW Checkpoint control and cancer RH Medema1,3 and L Macu˚rek2 1Department of Medical Oncology, University Medical Center, Utrecht, The Netherlands and 2Department of Genome Integrity, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic DNA-damaging therapies represent the most frequently efficient DNA repair has been recently reviewed used non-surgical anticancer strategies in the treatment of extensively elsewhere (Bekker-Jensen and Mailand, human tumors. These therapies can kill tumor cells, but at 2010; Ciccia and Elledge, 2010; Polo and Jackson, the same time they can be particularly damaging and 2011). This review will focus on the mechanisms that mutagenic to healthy tissues. The efficacy of DNA- activate checkpoints after genotoxic stress and silencing damaging treatments can be improved if tumor cell death of checkpoints during the recovery process that can is selectively enhanced, and the recent application of poly- occur after successful repair of the damage. (ADP-ribose) polymerase inhibitors in BRCA1/2-deficient tumors is a successful example of this. DNA damage is known to trigger cell-cycle arrest through activation of Activation of DNA-damage checkpoints DNA-damage checkpoints. This arrest can be reversed once the damage has been repaired, but irreparable In general, activation of DNA-damage checkpoints is damage can promote apoptosis or senescence. Alterna- enabled by recognition of DNA damage by sensors, tively, cells can reenter the cell cycle before repair has followed by an ordered activation of upstream and been completed, giving rise to mutations. In this review we effector kinases, the latter of which can directly target discuss the mechanisms involved in the activation and the major cell-cycle control machinery (Figure 1a). inactivation of DNA-damage checkpoints, and how the DNA damage can induce a cell-cycle arrest in the G1, transition from arrest and cell-cycle re-entry is controlled. intra-S or G2 phase of the cell cycle. Depending on the In addition, we discuss recent attempts to target the phase of the cell cycle when damage occurs, and the checkpoint in anticancer strategies. mode of DNA damage, cells can activate distinct Oncogene (2012) 31, 2601–2613; doi:10.1038/onc.2011.451; pathways in response to genotoxic stress. published online 3 October 2011 The primary response to DNA damage is accom- plished by upstream kinases of the phosphatidylinositol- Keywords: DNA damage; checkpoint; cancer; check- 3-OH kinase-related family, which includes ATM point recovery (ataxia teleangiectasia mutated kinase), ATR (ATM- and Rad3-related kinase) and DNA-PK (DNA-depen- dent protein kinase). Whereas ATM and DNA-PK are activated by double-strand breaks (DSBs), ATR re- Introduction sponds to a broader spectrum of DNA-damaging lesions that generate single-stranded DNA (including stalled To maintain genome integrity, cells need to adequately replication forks caused by bulky base adducts or UV respond to various modes of genotoxic stress. This is photoproducts). This simplistic view, however, is in fact achieved by activation of evolutionarily conserved more complex because DSBs are processed during the DNA-damage response (DDR) pathways that abrogate S/G2 phases of the cell cycle by the endonuclease CtIP cell-cycle progression when the genome is damaged and and generate single-stranded DNA lesions leading to a stimulate DNA repair. Depending on the extent of secondary activation of the ATR (Jazayeri et al., 2006; DNA damage, cells either manage to repair all lesions Sartori et al., 2007). All phosphatidylinositol-3-OH and re-enter the cell cycle (checkpoint recovery), or they kinases responding to DNA damage show similar are eliminated by programmed cell death (apoptosis). substrate specificities, and recent phosphoproteomic Alternatively, cells can remain permanently arrested screens reveal a substantial overlap of their substrates after a DNA-damaging insult (senescence). Activation (Matsuoka et al., 2007; Bennetzen et al., 2010; Bensimon of the components of DDR pathway that allows et al., 2010). The best example is probably the histone variant H2AX, which is rapidly phosphorylated at Correspondence: Dr L Macu˚rek, Department of Genome Integrity, Ser-139 (producing gH2AX) by ATM/ATR or DNA-PK Institute of Molecular Genetics, Academy of Sciences of the Czech in the chromatin flanking the damage site. On the other Republic, Videnska 1083, Prague 4 14200, Czech Republic. hand, these kinases also have some exclusive substrates, E-mail: [email protected] which are not shared by the other members. Thus ATM 3Current address: Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands phosphorylates checkpoint kinase-2 (Chk2) at Thr-68, Received 10 July 2011; revised 16 August 2011; accepted 29 August 2011; whereas ATR phosphorylates Chk1 at two residues, published online 3 October 2011 Ser-317 and Ser-345 (Bartek and Lukas, 2003). In general, Checkpoint control and cancer RH Medema and L Macu˚rek 2602 IR or chemotherapy UV or replication stress (Falck et al., 2005). Active ATM generates gH2AX at the surrounding chromatin, which is recognized by DSB ssDNA CtIP (S or G2 phase) RPA phosphopeptide-binding BRCT domains that are present MRN 9-1-1 H2AX ATRIP in many proteins involved in the DDR, and serves as a MDC1 TopBP1 docking site for a large adaptor protein, MDC1 (Stucki RHINO et al., 2005). Recruitment of multiple additional compo- ATM ATR p38 nents of the checkpoint then follows in an orderly Claspin Chk2 Mdm2 manner, including RNF8, RNF168, HERC2, 53BP1 and MK2 Chk1 BRCA1 (reviewed elsewhere Bekker-Jensen and Mai- p53 land, 2010). In general, recruitment of these proteins to Nek11 the chromatin is essential for efficient DNA repair and Bax GADD45 p21 Cdc25A/B/C Wee1 may also have some role in further amplification of the Noxa checkpoint signaling (that is, by recruiting more ATM) (Lee et al., 2010; Shibata et al., 2010). ATM is rapidly cyclin autophosphorylated at Ser-1981, which was originally APOPTOSIS Cdk proposed to induce the dissociation of an inactive CHECKPOINT MAINTENANCE homodimer into active monomers (Bakkenist and & SURVIVAL CHECKPOINT ARREST Kastan, 2003). However, mice lacking the corresponding ATM autophosphorylation sites are still able to fully Aurora-A activate the checkpoint after exposure to ionizing H2AX hBora radiation (IR), strongly suggesting that ATM autopho- ATM sphorylation is not an essential step for its activation Plk1 (but a useful marker of ATM activity) (Pellegrini et al., Mdm2 Wip1 MdmX 2006). Instead, DNA damage-induced acetylation of ATR ATM at Lys-3016 by the acetyltransferase Tip60 was Claspin recently proposed to activate the ATM (Sun et al., 2005, 2007). In this model, Tip60 is recruited to DSBs by a GTSE1 p53 Chk1 direct interaction with the Mre11–Rad50–Nbs1 complex and its enzymatic activity toward ATM is increased after binding of its chromodomain to trimethylated histone p21 Cdc25A/B/C Wee1 H3 (H3K9me3) (Sun et al., 2009; Chailleux et al., 2010). By contrast, single-stranded DNA lesions (such as the cyclin B stalled replication forks or resected DSBs) are rapidly Cdk1 coated by replication protein-A complexes, which further recruit and activate ATR in a stable complex CHECKPOINT RECOVERY with its cofactor ATRIP (Zou and Elledge, 2003). In parallel, replication protein-A binds to Rad17 and Figure 1 (a) Checkpoint activation. DNA damage is recognized by various sensor and adaptor proteins, which leads to activation of recruits a ring-shaped trimeric complex, Rad9–Hus1– ATM and ATR kinases and allows establishing of a DNA-damage Rad1 (9-1-1), to the site of damage. This 9-1-1 complex checkpoint. The major components activated during this response is then phosphorylated by ATR and can bind to the are Chk1 and p53 (green). Chk1 regulates cdc25A/B/C and Wee1, BRCT domains of an adaptor protein, TopBP1, which which leads to inhibitory phosphorylation of Cdk (yellow dots), further boosts the activity of ATR (Cimprich and prevents its activation (red) and causes cell-cycle arrest. p53 is stabilized by multiple posttranslational modifications (dots), and by Cortez, 2008). RHINO, a recently identified 9-1-1- and increasing the transcription of a Cdk inhibitor, p21, and repressing TopBP1-interacting protein, is required for efficient the transcription of cyclin-B, it contributes to inhibition of cyclin– activation of ATR (Cotta-Ramusino et al., 2011). Active Cdk. In addition, cells activate the Chk2 and p38/MK2 pathways ATR has several hundreds of substrates, including that are involved in apoptosis and checkpoint maintenance, Chk1, which is essential for induction of the checkpoint respectively. (b) Recovery from the G2 checkpoint. After DNA repair, multiple proteins are de-phosphorylated by Wip1 phospha- response. Importantly, Chk1 needs to form a complex tase, which leads to silencing of the checkpoint signaling and with a mediator protein, claspin, to be efficiently inactivation of p53. In parallel, Plk1 kinase targets claspin and activated by ATR (Chini and Chen, 2003; Kumagai Wee1 for degradation, and activates Cdc25A/B/C, which allows et al., 2004). Upon phosphorylation, Chk1 is released activation of cyclin-B–Cdk1 and checkpoint recovery. from the chromatin and can freely diffuse through the nucleus to phosphorylate multiple substrates to establish phosphorylation of Chk2 and Chk1
Load more

Recommended publications
  • Genetic and Genomic Analysis of Hyperlipidemia, Obesity and Diabetes Using (C57BL/6J × TALLYHO/Jngj) F2 Mice
    University of Tennessee, Knoxville TRACE: Tennessee Research and Creative Exchange Nutrition Publications and Other Works Nutrition 12-19-2010 Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P. Stewart Marshall University Hyoung Y. Kim University of Tennessee - Knoxville, [email protected] Arnold M. Saxton University of Tennessee - Knoxville, [email protected] Jung H. Kim Marshall University Follow this and additional works at: https://trace.tennessee.edu/utk_nutrpubs Part of the Animal Sciences Commons, and the Nutrition Commons Recommended Citation BMC Genomics 2010, 11:713 doi:10.1186/1471-2164-11-713 This Article is brought to you for free and open access by the Nutrition at TRACE: Tennessee Research and Creative Exchange. It has been accepted for inclusion in Nutrition Publications and Other Works by an authorized administrator of TRACE: Tennessee Research and Creative Exchange. For more information, please contact [email protected]. Stewart et al. BMC Genomics 2010, 11:713 http://www.biomedcentral.com/1471-2164/11/713 RESEARCH ARTICLE Open Access Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice Taryn P Stewart1, Hyoung Yon Kim2, Arnold M Saxton3, Jung Han Kim1* Abstract Background: Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/ JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia.
    [Show full text]
  • F-Box Protein FBXO31 Directs Degradation of MDM2 to Facilitate P53-Mediated Growth Arrest Following Genotoxic Stress
    F-box protein FBXO31 directs degradation of MDM2 to facilitate p53-mediated growth arrest following genotoxic stress Sunil K. Maloniaa,1, Parul Duttab, Manas Kumar Santrab,1,2, and Michael R. Greena,c,2 aDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; bNational Centre for Cell Science, University of Pune Campus, Ganeshkhind, Pune, Maharashtra 411007, India; and cHoward Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605 Contributed by Michael R. Green, June 4, 2015 (sent for review May 28, 2015; reviewed by Sanjeev Das and Kevin Struhl) The tumor suppressor p53 plays a critical role in maintaining genomic DNA damage there is a posttranslational increase of FBXO31 stability. In response to genotoxic stress, p53 levels increase and in- levels, as there is for p53 (9). These considerations prompted us to duce cell-cycle arrest, senescence, or apoptosis, thereby preventing ask whether there was a functional relationship between FBXO31 replication of damaged DNA. In unstressed cells, p53 is maintained and p53. at a low level. The major negative regulator of p53 is MDM2, an E3 ubiquitin ligase that directly interacts with p53 and promotes its Results polyubiquitination, leading to the subsequent destruction of p53 by FBXO31 Is Required for Decreased MDM2 and Increased p53 Levels the 26S proteasome. Following DNA damage, MDM2 is degraded Following DNA Damage. We asked whether the ability of FBXO31 rapidly, resulting in increased p53 stability. Because of the important to induce growth arrest results, at least in part, from the regulation role of MDM2 in modulating p53 function, it is critical to understand of p53 levels.
    [Show full text]
  • Human Lectins, Their Carbohydrate Affinities and Where to Find Them
    biomolecules Review Human Lectins, Their Carbohydrate Affinities and Where to Review HumanFind Them Lectins, Their Carbohydrate Affinities and Where to FindCláudia ThemD. Raposo 1,*, André B. Canelas 2 and M. Teresa Barros 1 1, 2 1 Cláudia D. Raposo * , Andr1 é LAQVB. Canelas‐Requimte,and Department M. Teresa of Chemistry, Barros NOVA School of Science and Technology, Universidade NOVA de Lisboa, 2829‐516 Caparica, Portugal; [email protected] 12 GlanbiaLAQV-Requimte,‐AgriChemWhey, Department Lisheen of Chemistry, Mine, Killoran, NOVA Moyne, School E41 of ScienceR622 Co. and Tipperary, Technology, Ireland; canelas‐ [email protected] NOVA de Lisboa, 2829-516 Caparica, Portugal; [email protected] 2* Correspondence:Glanbia-AgriChemWhey, [email protected]; Lisheen Mine, Tel.: Killoran, +351‐212948550 Moyne, E41 R622 Tipperary, Ireland; [email protected] * Correspondence: [email protected]; Tel.: +351-212948550 Abstract: Lectins are a class of proteins responsible for several biological roles such as cell‐cell in‐ Abstract:teractions,Lectins signaling are pathways, a class of and proteins several responsible innate immune for several responses biological against roles pathogens. such as Since cell-cell lec‐ interactions,tins are able signalingto bind to pathways, carbohydrates, and several they can innate be a immuneviable target responses for targeted against drug pathogens. delivery Since sys‐ lectinstems. In are fact, able several to bind lectins to carbohydrates, were approved they by canFood be and a viable Drug targetAdministration for targeted for drugthat purpose. delivery systems.Information In fact, about several specific lectins carbohydrate were approved recognition by Food by andlectin Drug receptors Administration was gathered for that herein, purpose. plus Informationthe specific organs about specific where those carbohydrate lectins can recognition be found by within lectin the receptors human was body.
    [Show full text]
  • Mouse Fbxo31 Conditional Knockout Project (CRISPR/Cas9)
    https://www.alphaknockout.com Mouse Fbxo31 Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Fbxo31 conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Fbxo31 gene (NCBI Reference Sequence: NM_133765 ; Ensembl: ENSMUSG00000052934 ) is located on Mouse chromosome 8. 9 exons are identified, with the ATG start codon in exon 1 and the TGA stop codon in exon 9 (Transcript: ENSMUST00000059018). Exon 3~4 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Fbxo31 gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP23-330D20 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Exon 3 starts from about 24.39% of the coding region. The knockout of Exon 3~4 will result in frameshift of the gene. The size of intron 2 for 5'-loxP site insertion: 5812 bp, and the size of intron 4 for 3'-loxP site insertion: 828 bp. The size of effective cKO region: ~1040 bp. The cKO region does not have any other known gene. Page 1 of 8 https://www.alphaknockout.com Overview of the Targeting Strategy Wildtype allele gRNA region 5' gRNA region 3' 1 3 4 5 9 Targeting vector Targeted allele Constitutive KO allele (After Cre recombination) Legends Exon of mouse Fbxo31 Homology arm cKO region loxP site Page 2 of 8 https://www.alphaknockout.com Overview of the Dot Plot Window size: 10 bp Forward Reverse Complement Sequence 12 Note: The sequence of homologous arms and cKO region is aligned with itself to determine if there are tandem repeats.
    [Show full text]
  • Regulation of the Mdm2-P53 Signaling Axis in the DNA Damage Response and Tumorigenesis
    Review Article Regulation of the Mdm2-p53 signaling axis in the DNA damage response and tumorigenesis Michael I. Carr, Stephen N. Jones Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA Contributions: (I) Conception and design: All authors; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: All authors; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Stephen N. Jones. Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA 01655, USA. Email: [email protected]. Abstract: The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage. Failure of the damaged cell to undergo growth arrest or apoptosis, or to respond to the DNA damage by other p53-coordinated mechanisms, can lead to inappropriate cell growth and tumorigenesis. In cells that have successfully responded to genetic damage, the amount of p53 present in the cell must return to basal levels in order for the cell to resume normal growth and function.
    [Show full text]
  • Disruption of Ubiquitin Mediated Proteolysis Is a Widespread Mechanism of Tumorigenesis
    bioRxiv preprint doi: https://doi.org/10.1101/507764; this version posted December 28, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Disruption of ubiquitin mediated proteolysis is a widespread mechanism of tumorigenesis Francisco Martínez-Jiménez1, Ferran Muiños1, Erika Lopez-Arribillaga1, Nuria Lopez-Bigas1,2,3,*,†, Abel Gonzalez-Perez1,2,*,† Affiliations: 1. Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain. 2. Research Program on Biomedical Informatics, Universitat Pompeu Fabra, Barcelona, Catalonia, Spain. 3. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain * Co-senior authors †Corresponding authors. E-mail: [email protected], [email protected] Abstract E3 ligases and degrons --the sequences they recognize in target proteins-- are key parts of the ubiquitin-mediated proteolysis system. There are several examples of alterations of these two components of the system that play a role in cancer. Here, we uncovered the landscape of the contribution of such alterations to tumorigenesis across cancer types. We first systematically identified novel instances of degrons across the human proteome using a random forest classifier, and validated them exploiting somatic mutations across more than 7,000 tumors. We detected signals of positive selection across these novel degrons and revealed new instances involved in cancer development. Overall, we estimated that at least one in seven driver mutations across primary tumors affect either degrons or E3 ligases.
    [Show full text]
  • The Role of Ubiquitination and Sumoylation in DNA Replication
    The Role of Ubiquitination and SUMOylation in DNA Replication Tarek Abbas1,2,3* 1Department of Radiation Oncology, University of Virginia, Charlotesville, VA, USA. 2Department of Biochemistry and Molecular Genetics, University of Virginia, Charlotesville, VA, USA. 3Center for Cell Signaling, University of Virginia, Charlotesville, VA, USA. *Correspondence: [email protected] htps://doi.org/10.21775/cimb.040.189 Abstract Regulation of eukaryotic DNA DNA replication is a tightly regulated conserved replication process that ensures the faithful transmission of genetic material to defne heritable phenotypic Initiation of DNA replication traits. Perturbations in this process result in Eukaryotic DNA replication is tightly regulated genomic instability, mutagenesis, and diseases, such that cells replicate their entire genome once including malignancy. Proteins involved in the and only once in a given cell cycle (Machida et initiation, progression, and termination of DNA al., 2005). For mammalian cells, this is no easy replication are subject to a plethora of revers- task since each proliferative somatic cell must ef- ible post-translational modifcations (PTMs) to ciently replicate approximately 6 billion base pairs provide a proper temporal and spatial control (in male cells) from roughly 250,000 replication of replication. Among these, modifcations origins scatered throughout the genome with involving the covalent atachment of the small each division cycle (Cadoret et al., 2008; Sequeira- protein ubiquitin or the small ubiquitin-like Mendes et al., 2009; Karnani et al., 2010). With modifer (SUMO) to replication and replication- roughly 600 million new blood cells born in the associated proteins are particularly important for bone marrow of an adult human (Doulatov et al., the proper regulation of DNA replication as well 2012), one cannot grasp the magnitude of the as for optimal cellular responses to replication task the replication machinery has to accomplish.
    [Show full text]
  • A Microrna/Ubiquitin Ligase Feedback Loop Regulates Slug
    Volume 19 Number xx Month 2017 pp. 483–495 483 www.neoplasia.com Rajesh Kumar Manne*, Yashika Agrawal*, A MicroRNA/Ubiquitin Ligase † Anil Bargale , Asha Patel*, Debasish Paul*, Feedback Loop Regulates Neha Anilkumar Gupta*, Srikanth Rapole*, Vasudevan Seshadri*, Deepa Subramanyam*, Slug-Mediated Invasion in Praveenkumar Shetty† and Manas Kumar Santra* Breast Cancer *National Centre for Cell Science, Pune University Campus, Ganesh khind, Pune, 411 007, Maharashtra, India; †Department of Biochemistry/Central Research Laboratory, SDM College of Medical Sciences & Hospital, Dharwad, Karnataka, India Abstract The transformation of a normal cell to cancer requires the derail of multiple pathways. Normal signaling in a cell is regulated at multiple stages by the presence of feedback loops, calibration of levels of proteins by their regulated turnover, and posttranscriptional regulation, to name a few. The tumor suppressor protein FBXO31 is a component of the SCF E3 ubiquitin ligase and is required to arrest cells at G1 following genotoxic stresses. Due to its growth- suppression activity, it is underexpressed in many cancers. However, the molecular mechanism underlying the translational regulation of FBXO31 remains unclear. Here we show that the oncogenic microRNAs miR-93 and miR-106a repress FBXO31, resulting in the upregulation of Slug, which is involved in epithelial-mesenchymal transition and cell invasion. FBXO31 targets and ubiquitylates Slug for proteasomal degradation. However, this mechanism is repressed in breast tumors where miR-93 and miR-106a are overexpressed. Our study further unravels an interesting mechanism whereby Slug drives the expression of miR-93 and miR-106a, thus establishing a positive feedback loop to maintain an invasive phenotype.
    [Show full text]
  • Regulatory Network Analysis of Genes and Micrornas in Human Hepatoblastoma
    ONCOLOGY LETTERS 12: 4099-4106, 2016 Regulatory network analysis of genes and microRNAs in human hepatoblastoma JIMIN HE1,3, XIAOXIN GUO1-3, LINLIN SUN2,3, NING WANG1,3 and JIWEI BAO2,3 1College of Computer Science and Technology; 2College of Software; 3Key Laboratory of Symbolic Computation and Knowledge Engineering of Ministry of Education, Jilin University, Changchun, Jilin 130012, P.R. China Received March 12, 2015; Accepted January 11, 2016 DOI: 10.3892/ol.2016.5196 Abstract. Hepatoblastoma (HB) is a common type of primary Homo sapiens (hsa)-miR-221, hsa-miR-18a and hsa-miR-17-5p, tumor in children. Previous studies have examined the expression but no miRNAs targeted MYCN. In conclusion, the pathways of genes, including transcription factors (TFs), target genes, host and mechanisms underlying HB were expounded in the present genes and microRNAs (miRNAs or miRs) associated with HB. study, which proposed a fundamental hypothesis for additional However, the regulatory pathways of miRNAs and genes remain studies. unclear. In the present study, a novel perspective is proposed, which focuses on HB and the associated regulatory pathways, Introduction to construct three networks at various levels, including a differ- entially expressed network, an associated network and a global Hepatoblastoma (HB) is the most common hepatic malig- network. Genes and miRNAs are considered as key factors in the nancy in children, and accounts for ~1% of all childhood network. In the three networks, the associations between each tumors (1). Usually, the disease is diagnosed during the first pair of factors, including TFs that regulate miRNAs, miRNAs three years of a child's life (2).
    [Show full text]
  • Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control
    molecules Review Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control Dulce Peris-Moreno , Laura Cussonneau, Lydie Combaret ,Cécile Polge † and Daniel Taillandier *,† Unité de Nutrition Humaine (UNH), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Clermont Auvergne, F-63000 Clermont-Ferrand, France; [email protected] (D.P.-M.); [email protected] (L.C.); [email protected] (L.C.); [email protected] (C.P.) * Correspondence: [email protected] † These authors contributed equally to the work. Abstract: Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramati- cally increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear.
    [Show full text]
  • Functional Analysis of ANKRD11 and FBXO31
    Functional Analysis of ANKRD11 and FBXO31: Two Candidate Tumour Suppressor Genes from the 16q24.3 Breast Cancer Loss of Heterozygosity Region Paul Matthew Neilsen B.Sc. B.Biomed.Sc. (Hon) Thesis submitted for the Degree of Doctor of Philosophy Breast Cancer Genetics Group Faculty of Health Sciences, School of Medicine, Discipline of Medicine, University of Adelaide, South Australia. Hanson Institute, Adelaide, South Australia. January 2008 This thesis is dedicated to my brother; Although you are no longer with us, your undying determination and passion for life remains with us all. You have always be my guiding light in times of dark, my guardian angel in the presence of evil. I know you will always be with me, and together we will walk, hand in hand, along the road towards a cure. II Table of Contents ABSTRACT VII DECLARATION IX LIST OF PUBLICATIONS X ABBREVIATIONS XI ACKNOWLEDGEMENTS XV CHAPTER 1: INTRODUCTION 1 1.1 – Cancer: a genetic disease 1 1.1.1 – Oncogenes and proto-oncogenes 1 1.1.2 – Tumour suppressor genes 2 1.1.2.1 – Inactivation of tumour suppressor genes 2 1.1.2.2 – Retinoblastoma as a model for Knudson’s “two-hit” hypothesis 7 1.1.2.3 – Epigenetic silencing of tumour suppressor genes 8 1.1.2.4 – Haploinsufficient tumour suppressor genes 9 1.2 – Breast cancer 11 1.2.1 – Estrogens and breast cancer 12 1.2.2 – Molecular basis of breast tumorigenesis 12 1.2.2.1 – Breast cancer oncogenes: ERBB2 / HER2 13 1.2.2.2 – Breast cancer oncogenes: CCND1 14 1.2.2.3 – Breast cancer oncogenes: MYC 15 1.2.2.4 – Breast Cancer Tumour Suppressor
    [Show full text]
  • Degradation of FBXO31 by APC/C Is Regulated by AKT- and ATM-Mediated Phosphorylation
    Degradation of FBXO31 by APC/C is regulated by AKT- and ATM-mediated phosphorylation Srinadh Chopparaa,b,1, Sunil K. Maloniac,d,1, Ganga Sankarana, Michael R. Greenc,d,2, and Manas Kumar Santraa,2 aCancer Biology and Epigenetics Laboratory, National Centre for Cell Science, Ganeshkhind, 411 007 Pune, India; bDepartment of Biotechnology, Pune University, Ganeshkhind, 411 077 Pune, India; cHoward Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA 01605; and dDepartment of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605 Contributed by Michael R. Green, December 19, 2017 (sent for review April 10, 2017; reviewed by Sathees C. Raghavan and Susanta Roychoudhury) The F-box protein FBXO31 is a tumor suppressor that is encoded in arrest and senescence through transcriptional activation of p21 and 16q24.3, for which there is loss of heterozygosity in various solid other p53 target genes. In p53-deficient cells following genotoxic tumors. FBXO31 serves as the substrate-recognition component of stress, FBXO31 interacts with and mediates degradation of cyclin the SKP/Cullin/F-box protein class of E3 ubiquitin ligases and has D1, an important regulator of the G1/S transition, resulting in G1 been shown to direct degradation of pivotal cell-cycle regulatory arrest (11). FBXO31 has also been shown to target several other proteins including cyclin D1 and the p53 antagonist MDM2. FBXO31 proteins, including the DNA replication factor CDT1 (12), the levels are normally low but increase substantially following genotoxic mitotic regulator FOXM1 (13), and the p38 activator MKK6 (14). stress through a mechanism that remains to be determined.
    [Show full text]