DOCSLIB.ORG

Alternative Pathways for the Extension of Cellular Life Span: Inactivation of P53/Prb and Expression of Telomerase

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Alternative Pathways for the Extension of Cellular Life Span: Inactivation of P53/Prb and Expression of Telomerase Oncogene (1999) 18, 7676 ± 7680 ã 1999 Stockton Press All rights reserved 0950 ± 9232/99 $15.00 http://www.stockton-press.co.uk/onc Alternative pathways for the extension of cellular life span: inactivation of p53/pRb and expression of telomerase Homayoun Vaziri1 and Samuel Benchimol*,2,3 1Stanford University School of Medicine, Department of Molecular Pharmacology, Edward's Building, 300 Pasteur Drive Stanford, California, CA 94305-5332, USA; 2Ontario Cancer Institute/Princess Margaret Hospital, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G-2M9; 3Department of Medical Biophysics, University of Toronto, 610 University Avenue, Toronto, Ontario, Canada M5G-2M9 Telomere shortening may be one of several factors that A provocative and in¯uential model of cell contribute to the onset of senescence in human cells. The senescence and immortalization (Harley et al., 1992) p53 and pRb pathways are involved in the regulation of suggested that telomeres shorten in many proliferating cell cycle progression from G1 into S phase and somatic cells due to the end replication problem (the inactivation of these pathways leads to extension of life inability of the DNA replication machinery to span. Short dysfunctional telomeres may be perceived as completely copy chromosomal termini) (Olovnikov, damaged DNA and may activate these pathways, leading 1973; Watson, 1972). In this model, shortened to prolonged arrest in G1, typical of cells in senescence. telomeres signal the onset of senescence. Cells with Inactivation of the p53 and pRb pathways, however, does an extended life span bypass the senescence signal but not lead to cell immortalization. Cells that overcome continue to lose telomeric DNA until they reach crisis senescence and have an extended life span continue to and die. Overcoming crisis is associated with main- lose telomeric DNA and subsequently enter a second tenance of telomere length and reactivation of phase of growth arrest termed `crisis'. Forced expression telomerase (Counter et al., 1992). Although some of telomerase in human cells leads to the elongation of similarities exist between senescence and crisis, there telomeres and immortalization. The development of is now abundant evidence demonstrating that these human cancer is frequently associated with the inactiva- represent fundamentally dierent cellular processes tion of the pRb and p53 pathways, attesting to the governed by distinct genetic regulatory components. importance of senescence in restricting the tumor- forming ability of human cells. Cancer cells must also maintain telomere length and, in the majority of cases, Involvement of the p53 and Rb pathways in senescence this is associated with expression of telomerase activity. The transforming proteins of DNA tumor viruses such Keywords: telomerase; hTERT; telomere; senescence; as SV40 large T antigen, adenovirus E1A/E1B or HPV aging; p53; pRb; TIEL; PARP E6/E7 can extend the life span of human cells in culture, but only a few, exceptional clones emerge as survivors following crisis. Extension of cellular life span is dependent on the ability of these viral proteins Two proliferative blockades: senescence and crisis to target the tumor suppressor proteins, p53 and pRb, and render them functionally inactive. In contrast to rodent cells, human cells rarely become pRb and p53 are important regulators of cell cycle immortal in culture. This dierence may be attributed, progression and play key roles in controlling entry into at least partially, to the Hay¯ick barrier also termed S phase. pRb binds to members of the E2F family of `senescence'. In 1961, Hay¯ick showed that normal transcription factors. In the bound state, E2F-1 is human cells divide only a ®nite number of times in unable to activate E2F-1-responsive genes required for culture and undergo replicative senescence (Hay¯ick entry into S phase and for DNA synthesis. Phosphor- and Moorhead, 1961). Spontaneous escape from ylation of pRb by the G1 cyclin-dependent kinases senescence in human cells is an extremely rare event (CDKs) releases E2F-1 in a transcriptionally active but this can be facilitated through the action of certain form, allowing cells to progress from G1 into S phase. oncogenes or by exposure of primary cells to various The HPV E7 protein, as well as SV40 large T antigen mutagens. Cells that overcome senescence and have an and adenovirus E1A, override this control circuit by extended life span subsequently enter a second phase of binding to pRb and causing the inappropriate release growth arrest termed `crisis'. Unlike senescent cells that of active E2F-1 in the absence of CDK-mediated are primarily arrested in the G1 phase of the cell cycle, phosphorylation of pRb (Weinberg, 1995). cells at crisis undergo division and death. Escape from p53 promotes G1 cell cycle arrest or apoptosis in crisis occurs at very low frequency (361077) (Shay and response to DNA damage and other forms of stress Wright, 1989). (Levine, 1997). p53 protein functions as a transcription factor by binding to speci®c DNA sequences and regulating the transcription of target genes. This activity of p53 is considered to be important for its tumor suppressor function since most of the mutations *Correspondence: S Benchimol in the p53 gene in human cancer eliminate the ability Extension of cellular life span H Vaziri and S Benchimol 7677 of p53 protein to bind DNA or to promote cells (Vaziri et al., 1993) and endothelial cells (Chang transcription. p53 blocks cells in G1 primarily through and Harley, 1995). Several hypotheses have been its ability to induce expression of p21WAF1, a CDK proposed to explain how shortened telomeres might inhibitor (E1-Deiry et al., 1993). p21WAF1 provides a lead to senescence. We proposed that shortened link between the p53 and Rb regulatory pathways. telomeres per se are not the signal for senescence; p21WAF1 can act to limit the phosphorylation of pRb, rather that shortened telomeres compromise DNA thereby preventing cells from exiting the G1 phase of integrity and generate strand breaks that are sensed the cell cycle. The HPV E6 protein binds to p53 and by the DNA damage recognition machinery of the cell, promotes its degradation via the ubiquitin proteolytic leading to p53 activation and p21WAF1-mediated G1 pathway, while adenovirus E1B and SV40 large T arrest (Vaziri and Benchimol, 1996). In search of other antigen bind to p53 and block its transcriptional eector molecules in this pathway, we found that activity. In the absence of p53, pRb or p21WAF1, the inhibition of poly(ADP-ribosyl)ation in normal human cell cycle arrest pathway induced by DNA damage is ®broblasts extended cellular life span signi®cantly. lost (Kastan et al., 1992; Brugarolas et al., 1995; Deng Importantly, we demonstrated a physical and func- et al., 1995; Harrington et al., 1998). tional association between poly(ADP-ribose) polymer- Increased expression and/or activity of p53, p21 and ase and p53 in human cells (Vaziri et al., 1997). Hence another CDK inhibitor, p16INK4a, is detected in it is possible that short and dysfunctional telomeres senescent cells lending further support to the impor- signal growth arrest via poly(ADP-ribosyl)ation of tance of the p53 and Rb pathways in senescence critical eector molecules including p53. (Atadja et al., 1995; Noda et al., 1994; Kulju and Lehman, 1995; Vaziri et al., 1997; Alcorta et al., 1996; Hara et al., 1996). The mouse INK4a locus encodes the The telomerase complex CDK inhibitor, p16INK4a, as well as an unrelated protein, p19ARF which arises in large part from an Synthesis of telomeric repeats at the ends of chromo- alternative reading frame (Quelle et al., 1995). In somes is performed by the telomerase protein/RNA human cells, usage of an alternative reading frame in complex. Telomerase activity, measured by the ability of the INK4a locus similarly gives rise to the human the enzyme to add TTAGGG repeats to the end of homolog known as p14ARF. Ectopic overexpression of synthetic telomeric DNA, was originally discovered in p53, p21, p16INK4a,orp19ARF/p14ARF in proliferating the ciliate Tetrahymena (Greider and Blackburn, 1985) cells can induce G1 arrest. The ability of p16INK4a to and subsequently in the human immortal cell line HeLa induce cell cycle arrest is pRb dependent while p19ARF- (Morin, 1989), The ground breaking discovery of or p14ARF- induced cell cycle arrest is p53 dependent. Euplotes p123, the catalytic subunit of telomerase The human and mouse ARF proteins have been shown (Lingner et al., 1997), led to identi®cation of the human to stabilize and activate p53. This occurs, at least in telomerase catalytic subunit (hTERT) (Harrington et al., part, by the interaction of the ARF proteins with 1997b; Kilian et al., 1997; Meyerson et al., 1997; MDM2 resulting in abrogation of MDM2's ability to Nakamura et al., 1997). The human telomerase complex promote the degradation of p53 (Pomerantz et al., consists of an RNA subunit named hTR (Feng et al., 1998; Zhang et al., 1998; Kamijo et al., 1998). Primary 1995) and hTERT. Several other proteins have also been murine ®broblasts lacking p53 or p19ARF or both identi®ed that interact with the telomerase complex p16INK4a and p19ARF are easily established into including TEP1/TLP1 (Harrington et al., 1997a). immortal cell lines (Harvey et al., 1993; Serrano et Evidence from S. cerevisiae and Euplotes suggests that al., 1996; Kamijo et al., 1997). several other factors could also potentially interact and In human ®broblasts derived from patients with Li- be a part of the complex, including EST1, EST4 and p43 Fraumeni syndrome that are heterozygous for wild- (Nugent and Lundblad, 1998). type p53, senescence can be overcome (Bischo et al., 1990) through loss or mutation of the remaining wild- type p53 allele (Rogan et al., 1995). In addition, Telomerase and extension of life span dominant negative inhibition of p53 protein (Bond et al., 1994) or inactivation of p21WAF1 (Brown et al., Reconstitution of telomerase activity in vitro requires 1997) in human cells can also overcome senescence and the RNA template of human telomerase hTR and the lead to an extended life span.
Load more

Recommended publications
  • Mitochondrial Metabolism and Cancer
    Cell Research (2018) 28:265-280. REVIEW www.nature.com/cr Mitochondrial metabolism and cancer Paolo Ettore Porporato1, *, Nicoletta Filigheddu2, *, José Manuel Bravo-San Pedro3, 4, 5, 6, 7, Guido Kroemer3, 4, 5, 6, 7, 8, 9, Lorenzo Galluzzi3, 10, 11 1Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, 10124 Torino, Italy; 2Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy; 3Université Paris Descartes/Paris V, Sorbonne Paris Cité, 75006 Paris, France; 4Université Pierre et Marie Curie/Paris VI, 75006 Paris, France; 5Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, 75006 Paris, France; 6INSERM, U1138, 75006 Paris, France; 7Meta- bolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, 94805 Villejuif, France; 8Pôle de Biologie, Hopitâl Européen George Pompidou, AP-HP, 75015 Paris, France; 9Department of Women’s and Children’s Health, Karolinska University Hospital, 17176 Stockholm, Sweden; 10Department of Radiation Oncology, Weill Cornell Medical College, New York, NY 10065, USA; 11Sandra and Edward Meyer Cancer Center, New York, NY 10065, USA Glycolysis has long been considered as the major metabolic process for energy production and anabolic growth in cancer cells. Although such a view has been instrumental for the development of powerful imaging tools that are still used in the clinics, it is now clear that mitochondria play a key role in oncogenesis. Besides exerting central bioen- ergetic functions, mitochondria provide indeed building blocks for tumor anabolism, control redox and calcium ho- meostasis, participate in transcriptional regulation, and govern cell death. Thus, mitochondria constitute promising targets for the development of novel anticancer agents.
    [Show full text]
  • CATALOG NUMBER: AKR-213 STORAGE: Liquid Nitrogen Note
    CATALOG NUMBER: AKR-213 STORAGE: Liquid nitrogen Note: For best results begin culture of cells immediately upon receipt. If this is not possible, store at -80ºC until first culture. Store subsequent cultured cells long term in liquid nitrogen. QUANTITY & CONCENTRATION: 1 mL, 1 x 106 cells/mL in 70% DMEM, 20% FBS, 10% DMSO Background HeLa cells are the most widely used cancer cell lines in the world. These cells were taken from a lady called Henrietta Lacks from her cancerous cervical tumor in 1951 which today is known as the HeLa cells. These were the very first cell lines to survive outside the human body and grow. Both GFP and blasticidin-resistant genes are introduced into parental HeLa cells using lentivirus. Figure 1. HeLa/GFP Cell Line. Left: GFP Fluorescence; Right: Phase Contrast. Quality Control This cryovial contains at least 1.0 × 106 HeLa/GFP cells as determined by morphology, trypan-blue dye exclusion, and viable cell count. The HeLa/GFP cells are tested free of microbial contamination. Medium 1. Culture Medium: D-MEM (high glucose), 10% fetal bovine serum (FBS), 0.1 mM MEM Non- Essential Amino Acids (NEAA), 2 mM L-glutamine, 1% Pen-Strep, (optional) 10 µg/mL Blasticidin. 2. Freeze Medium: 70% DMEM, 20% FBS, 10% DMSO. Methods Establishing HeLa/GFP Cultures from Frozen Cells 1. Place 10 mL of complete DMEM growth medium in a 50-mL conical tube. Thaw the frozen cryovial of cells within 1–2 minutes by gentle agitation in a 37°C water bath. Decontaminate the cryovial by wiping the surface of the vial with 70% (v/v) ethanol.
    [Show full text]
  • How Accurate Are Cancer Cell Lines? Some Argue That Tumour Cells Obtained Directly from Patients Are the Best Way to Study Cancer Genomics
    NEWS NATURE|Vol 463|18 February 2010 How accurate are cancer cell lines? Some argue that tumour cells obtained directly from patients are the best way to study cancer genomics. For decades, cancer cell cultures grown in Petri dishes have been the foundation of can- cer biology and the quest for drug treatments. But now that biologists are exploring cancer genomes, some are asking whether they should pursue a more expensive, less proven strategy RF.COM/SPL MEDICAL that may give a truer picture of key muta- tions: sequencing cells from tumours plucked directly from patients. Of the first six cancer genome sequences to be published, three have come from estab- lished cell lines and three from primary tumours. Hundreds more sequences are expected soon, both from individual labs and from major efforts such as the Cancer Genome Atlas in Bethesda, Maryland. And although most researchers continue to have a foot in both camps, the atlas project excludes work on cell lines. The major criticism of cell lines is that not all cancer types can be grown indefinitely in the laboratory. Those that do grow differ genetically from primary tissue, accumulating new mutations as they adapt to their artificial Cultured cancer cells might have different genetic characteristics from in situ tumours. environment. When implanted in rodents, brain-cancer cell lines tend to form a ‘bowling the University of California, Los Angeles, it in the cancer genome, says Stratton. His group ball’ mass of cells rather than infiltrating the will take thousands of comparisons between can then distinguish between segments of the brain like a spider web, as they do in humans, tumour sequences and normal DNA to equal genome that are lost as a result of breakage says Howard Fine, head of neuro-oncology at the benefit of sequencing the top 100 cell lines, from those in which a tumour-suppressing the National Institutes of Health in Bethesda.
    [Show full text]
  • Molecular Evolutionary Analysis of Plastid Genomes in Nonphotosynthetic Angiosperms and Cancer Cell Lines
    The Pennsylvania State University The Graduate School Department or Biology MOLECULAR EVOLUTIONARY ANALYSIS OF PLASTID GENOMES IN NONPHOTOSYNTHETIC ANGIOSPERMS AND CANCER CELL LINES A Dissertation in Biology by Yan Zhang 2012 Yan Zhang Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy Dec 2012 The Dissertation of Yan Zhang was reviewed and approved* by the following: Schaeffer, Stephen W. Professor of Biology Chair of Committee Ma, Hong Professor of Biology Altman, Naomi Professor of Statistics dePamphilis, Claude W Professor of Biology Dissertation Adviser Douglas Cavener Professor of Biology Head of Department of Biology *Signatures are on file in the Graduate School iii ABSTRACT This thesis explores the application of evolutionary theory and methods in understanding the plastid genome of nonphotosynthetic parasitic plants and role of mutations in tumor proliferations. We explore plastid genome evolution in parasitic angiosperms lineages that have given up the primary function of plastid genome – photosynthesis. Genome structure, gene contents, and evolutionary dynamics were analyzed and compared in both independent and related parasitic plant lineages. Our studies revealed striking similarities in changes of gene content and evolutionary dynamics with the loss of photosynthetic ability in independent nonphotosynthetic plant lineages. Evolutionary analysis suggests accelerated evolution in the plastid genome of the nonphotosynthetic plants. This thesis also explores the application of phylogenetic and evolutionary analysis in cancer biology. Although cancer has often been likened to Darwinian process, very little application of molecular evolutionary analysis has been seen in cancer biology research. In our study, phylogenetic approaches were used to explore the relationship of several hundred established cancer cell lines based on multiple sequence alignments constructed with variant codons and residues across 494 and 523 genes.
    [Show full text]
  • Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy
    cancers Review Mitochondrial Metabolism in Carcinogenesis and Cancer Therapy Hadia Moindjie 1,2, Sylvie Rodrigues-Ferreira 1,2,3 and Clara Nahmias 1,2,* 1 Inserm, Institut Gustave Roussy, UMR981 Biomarqueurs Prédictifs et Nouvelles Stratégies Thérapeutiques en Oncologie, 94800 Villejuif, France; [email protected] (H.M.); [email protected] (S.R.-F.) 2 LabEx LERMIT, Université Paris-Saclay, 92296 Châtenay-Malabry, France 3 Inovarion SAS, 75005 Paris, France * Correspondence: [email protected]; Tel.: +33-142-113-885 Simple Summary: Reprogramming metabolism is a hallmark of cancer. Warburg’s effect, defined as increased aerobic glycolysis at the expense of mitochondrial respiration in cancer cells, opened new avenues of research in the field of cancer. Later findings, however, have revealed that mitochondria remain functional and that they actively contribute to metabolic plasticity of cancer cells. Understand- ing the mechanisms by which mitochondrial metabolism controls tumor initiation and progression is necessary to better characterize the onset of carcinogenesis. These studies may ultimately lead to the design of novel anti-cancer strategies targeting mitochondrial functions. Abstract: Carcinogenesis is a multi-step process that refers to transformation of a normal cell into a tumoral neoplastic cell. The mechanisms that promote tumor initiation, promotion and progression are varied, complex and remain to be understood. Studies have highlighted the involvement of onco- genic mutations, genomic instability and epigenetic alterations as well as metabolic reprogramming, Citation: Moindjie, H.; in different processes of oncogenesis. However, the underlying mechanisms still have to be clarified. Rodrigues-Ferreira, S.; Nahmias, C. Mitochondria are central organelles at the crossroad of various energetic metabolisms.
    [Show full text]
  • Human Mitochondrial Peptide Deformylase, a New Anticancer Target of Actinonin-Based Antibiotics Mona D
    Research article Human mitochondrial peptide deformylase, a new anticancer target of actinonin-based antibiotics Mona D. Lee,1,2 Yuhong She,1 Michael J. Soskis,3 Christopher P. Borella,4 Jeffrey R. Gardner,1 Paula A. Hayes,1 Benzon M. Dy,1 Mark L. Heaney,5 Mark R. Philips,3 William G. Bornmann,4 Francis M. Sirotnak,1,2 and David A. Scheinberg1,2,5 1Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. 2Department of Pharmacology, Weill Graduate School of Medical Sciences of Cornell University, New York, New York, USA. 3Department of Medicine, New York University School of Medicine, New York, New York, USA. 4Organic Synthesis Core Facility, and 5Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. Peptide deformylase activity was thought to be limited to ribosomal protein synthesis in prokaryotes, where new peptides are initiated with an N-formylated methionine. We describe here a new human peptide defor- mylase (Homo sapiens PDF, or HsPDF) that is localized to the mitochondria. HsPDF is capable of removing formyl groups from N-terminal methionines of newly synthesized mitochondrial proteins, an activity previ- ously not thought to be necessary in mammalian cells. We show that actinonin, a peptidomimetic antibiotic that inhibits HsPDF, also inhibits the proliferation of 16 human cancer cell lines. We designed and synthesized 33 chemical analogs of actinonin; all of the molecules with potent activity against HsPDF also inhibited tumor cell growth, and vice versa, confirming target specificity. Small interfering RNA inhibition of HsPDF protein expression was also antiproliferative.
    [Show full text]
  • Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models
    biomolecules Article Effect of Erufosine on Membrane Lipid Order in Breast Cancer Cell Models 1, 1, 2 1 Rumiana Tzoneva y, Tihomira Stoyanova y, Annett Petrich , Desislava Popova , Veselina Uzunova 1 , Albena Momchilova 1 and Salvatore Chiantia 2,* 1 Bulgarian Academy of Sciences, Institute of Biophysics and Biomedical Engineering, 1113 Sofia, Bulgaria; [email protected] (R.T.); [email protected] (T.S.); [email protected] (D.P.); [email protected] (V.U.); [email protected] (A.M.) 2 Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Street 24-25, 14476 Potsdam, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-331-9775872 These author contribute equally to this work. y Received: 2 April 2020; Accepted: 19 May 2020; Published: 22 May 2020 Abstract: Alkylphospholipids are a novel class of antineoplastic drugs showing remarkable therapeutic potential. Among them, erufosine (EPC3) is a promising drug for the treatment of several types of tumors. While EPC3 is supposed to exert its function by interacting with lipid membranes, the exact molecular mechanisms involved are not known yet. In this work, we applied a combination of several fluorescence microscopy and analytical chemistry approaches (i.e., scanning fluorescence correlation spectroscopy, line-scan fluorescence correlation spectroscopy, generalized polarization imaging, as well as thin layer and gas chromatography) to quantify the effect of EPC3 in biophysical models of the plasma membrane, as well as in cancer cell lines. Our results indicate that EPC3 affects lipid–lipid interactions in cellular membranes by decreasing lipid packing and increasing membrane disorder and fluidity. As a consequence of these alterations in the lateral organization of lipid bilayers, the diffusive dynamics of membrane proteins are also significantly increased.
    [Show full text]
  • Cell and Tissue Polarity As a Non-Canonical Tumor Suppressor
    Commentary 1141 Cell polarity and cancer – cell and tissue polarity as a non-canonical tumor suppressor Minhui Lee1,2 and Valeri Vasioukhin1,3,* 1Division of Human Biology, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N., C3-168, Seattle, WA 98109, USA 2Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98109, USA 3Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA *Author for correspondence (e-mail: [email protected]) Accepted 19 February 2008 Journal of Cell Science 121, 1141-1150 Published by The Company of Biologists 2008 doi:10.1242/jcs.016634 Summary Correct establishment and maintenance of cell polarity is and differentiation of cancer stem cells. Data from in vivo and required for the development and homeostasis of all three-dimensional (3D) cell-culture models demonstrate that metazoans. Cell-polarity mechanisms are responsible not only tissue organization attenuates the phenotypic outcome of for the diversification of cell shapes but also for regulation of oncogenic signaling. We suggest that polarized 3D tissue the asymmetric cell divisions of stem cells that are crucial for organization uses cell-cell and cell-substratum adhesion their correct self-renewal and differentiation. Disruption of cell structures to reinforce and maintain the cell polarity of pre- polarity is a hallmark of cancer. Furthermore, recent evidence cancerous cells. In this model, polarized 3D tissue organization indicates that loss of cell polarity is intimately involved in functions as a non-canonical tumor suppressor that prevents cancer: several crucial cell-polarity proteins are known proto- the manifestation of neoplastic features in mutant cells and, oncogenes or tumor suppressors, basic mechanisms of cell ultimately, suppresses tumor development and progression.
    [Show full text]
  • The Genomic Landscape of Centromeres in Cancers Anjan K
    www.nature.com/scientificreports OPEN The Genomic Landscape of Centromeres in Cancers Anjan K. Saha 1,2,3, Mohamad Mourad3, Mark H. Kaplan3, Ilana Chefetz4, Sami N. Malek3, Ronald Buckanovich5, David M. Markovitz2,3,6,7 & Rafael Contreras-Galindo3,4 Received: 8 March 2019 Centromere genomics remain poorly characterized in cancer, due to technologic limitations in Accepted: 23 July 2019 sequencing and bioinformatics methodologies that make high-resolution delineation of centromeric Published: xx xx xxxx loci difcult to achieve. We here leverage a highly specifc and targeted rapid PCR methodology to quantitatively assess the genomic landscape of centromeres in cancer cell lines and primary tissue. PCR- based profling of centromeres revealed widespread heterogeneity of centromeric and pericentromeric sequences in cancer cells and tissues as compared to healthy counterparts. Quantitative reductions in centromeric core and pericentromeric markers (α-satellite units and HERV-K copies) were observed in neoplastic samples as compared to healthy counterparts. Subsequent phylogenetic analysis of a pericentromeric endogenous retrovirus amplifed by PCR revealed possible gene conversion events occurring at numerous pericentromeric loci in the setting of malignancy. Our fndings collectively represent a more comprehensive evaluation of centromere genetics in the setting of malignancy, providing valuable insight into the evolution and reshufing of centromeric sequences in cancer development and progression. Te centromere is essential to eukaryotic biology due to its critical role in genome inheritance1,2. Te nucleic acid sequences that dominate the human centromeric landscape are α-satellites, arrays of ~171 base-pair monomeric units arranged into higher-order arrays throughout the centromere of each chromosome3–103 1–3.
    [Show full text]
  • Transposable Elements in Cancer and Other Human Diseases Benoît Chénais
    Transposable Elements in Cancer and Other Human Diseases Benoît Chénais To cite this version: Benoît Chénais. Transposable Elements in Cancer and Other Human Diseases. Cur- rent Cancer Drug Targets, Bentham Science Publishers, 2015, 15 (3), pp.227 - 242. 10.2174/1568009615666150317122506. hal-01905441 HAL Id: hal-01905441 https://hal.archives-ouvertes.fr/hal-01905441 Submitted on 25 Oct 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Mini review: Transposable Elements in Cancer and other Human Diseases Benoît Chénais* Mer Molécules Santé EA2160, UFR Sciences et Techniques, Université du Maine, Le Mans, France. *Corresponding Author: Chénais B., Mer Molécules Santé, UFR Sciences et Techniques, Université du Maine, Avenue Olivier Messiaen, F-72085 Le Mans Cedex, France, Tel:+33- 243-833-25; fax +33-243-833-917; Email: [email protected] Abstract: Transposable elements (TEs) are mobile DNA sequences representing a substantial fraction of most genomes. Through the creation of new genes and functions, TEs are important elements of genome plasticity and evolution. However TE insertion in human genomes may be the cause of genetic dysfunction and alteration of gene expression contributing to cancer and other human diseases.
    [Show full text]
  • Regulation of the Cancer Cell Membrane Lipid Composition by Nacholeate☆ Effects on Cell Signaling and Therapeutical Relevance in Glioma
    Biochimica et Biophysica Acta 1838 (2014) 1619–1627 Contents lists available at ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbamem Review Regulation of the cancer cell membrane lipid composition by NaCHOleate☆ Effects on cell signaling and therapeutical relevance in glioma Victoria Lladó a,DavidJ.Lópeza, Maitane Ibarguren a, María Alonso a, Joan B. Soriano c, Pablo V. Escribá a, Xavier Busquets b,⁎ a Laboratory of Molecular Cell Biomedicine, University of the Balearic Islands—Lipopharma Therapeutics, S.L., Palma, Spain b Cell Biology (IUNICS), University of the Balearic Islands—Lipopharma Therapeutics, S.L., Palma, Spain c Epidemiology and Clinical Research, CIMERA, Mallorca, Spain article info abstract Article history: This review summarizes the cellular bases of the effects of NaCHOleate (2-hydroxyoleic acid; 2OHOA; Minerval) Received 9 October 2013 against glioma and other types of tumors. NaCHOleate, activates sphingomyelin synthase (SGMS) increasing the Received in revised form 20 January 2014 levels of cell membrane sphingomyelin (SM) and diacylglycerol (DAG) together with reductions of phosphatidyl- Accepted 22 January 2014 ethanolamine (PE) and phosphatidylcholine (PC). The increases in the membrane levels of NaCHOleate itself and Available online 10 February 2014 of DAG induce a translocation and overexpression of protein kinase C (PKC) and subsequent reductions of Cyclin D, cyclin-dependent kinases 4 and 6 (CDKs 4 and 6), hypophosphorylation of the retinoblastoma protein, inhibi- Keywords: Brain cancer tion of E2F1 and knockdown of dihydrofolate reductase (DHFR) impairing DNA synthesis. In addition in some Cancer therapy cancer cells, the increases in SM are associated with Fas receptor (FasR) capping and ligand-free induction of ap- Cell membrane optosis.
    [Show full text]
  • CANCER RESEARCH the Relationship of the Cell Cycle To
    CANCER RESEARCH VOLUME 25 JUNE 1965 NUMBER 5 The Relationship of the Cell Cycle to Tumor Growth and Control of Cell Division: A Review RENArO BASERGA' (Department of Pathology, Northwestern University Medical School, Chicago, Illinois) SUMMARY Metabolic activities of cells during interphase can be studied by high-resolution autoradiography with tritium-labeled precursors of nucleic acids and proteins. After completion of mitosis, offspring of the parent cell may divide again, or may differentiate and die without further division. Dividing cells go through a series of metabolic changes which constitute the cell cycle. The cell cycle is subdivided into 4 distinct phases: (a) a postmitotic phase called G,, during which the cell synthesizes ribo nucleic acid (RNA) and proteins; (b) an S phase, during which the amount of de oxyribonuleic acid (DNA) is duplicated while protein and RNA syntheses continue; (c) a postsynthetic phase, called G2, characterized by no net synthesis of DNA and con tinued RNA and protein synthesis as in postmitotic phase; and (d) mitosis, extending from beginning of prophase to completion of telophase during which there is no DNA synthesis, protein synthesis is reduced to a minimum, and RNA synthesis is limited to early prophase and late telophase. The length of the cell cycle and its 4 phases can be obtained by appropriate experimentation with labeled thymidine, a precursor of DNA, andhigh-resolutionautoradiography. Although thelengthof the ceilcycle variesin dif ferent kinds of cells, it is shorter in certain cells of the adult animal than in some of the fastest growing tumors. Tumor growth, therefore, must involve other kinetic param eters besides speed of cell proliferation.
    [Show full text]