DOCSLIB.ORG

Tumor Dedifferentiation: Diagnostic and Therapeutic Implications Jha Abhimanyu1 1Department of Pathology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Tumor Dedifferentiation: Diagnostic and Therapeutic Implications Jha Abhimanyu1 1Department of Pathology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal Journal of Pathology of Nepal (2017) Vol. 7, 1202 - 1210 cal Patholo Journal of lini gis f C t o o f N n e io p t a a l i - c 2 o 0 s 1 s 0 PATHOLOGY A N u e d p a n of Nepal l a M m e h d t i a c K al , A ad ss o oc n R www.acpnepal.com iatio bitio n Building Exhi Review Article Tumor dedifferentiation: diagnostic and therapeutic implications Jha Abhimanyu1 1Department of Pathology, Tribhuvan University Teaching Hospital, Kathmandu, Nepal. ABSTRACT Keywords: Carcinoma; Some of the neoplasm especially malignant tumors are notorious in masquerading their cell of origin Dedifferentiation; because of additional mutations which drives them to differentiate into unusual phenotype. This is Liposarcoma; implicated to a phenomenon of tumor dedifferentiation which can mislead into inappropriate categorization Melanoma; and therapy. Dedifferentiation is well recognized in sarcomas such as liposarcoma, chondrosarcoma and Sarcoma; malignant peripheral nerve sheath tumor. However, it can also develop in carcinomas, melanomas and lymphomas at initial diagnosis, following therapy or at recurrence. The phenomenon has been reported in both primary tumors as well as at metastatic foci. A correct and early pathological identification of this phenomenon might profoundly help in guiding appropriate therapy. Clinical and radiological findings, immunohistochemistry and genetic analysis are often required for correct lineage identification of these tumors. Correspondence: INTRODUCTION Dr. Abhimanyu Jha, MD Associate Professor, Department of Pathology Malignant tumors are notorious in masquerading their cell Tribhuvan University Teaching Hospital, Maharajgunj, Kathmandu, Nepal of origin, because of additional mutations, which drives ORCID ID: 0000-0003-4477-6129 them to differentiate into unusual phenotype. This is Email: [email protected] implicated to a ‘phenomenon’ of tumor ‘dedifferentiation’ which can mislead into inappropriate categorization and Reveived : July 15th, 2017 ; Accepted : August 8th, 2017; Published : September 1, 2017 therapy. Dedifferentiation is well recognized in sarcomas. Citation: Jha A. Tumor dedifferentiation: diagnostic and therapeutic implications. J Pathol Nep. However, it can develop in carcinomas, lymphomas 1-3 2017;7: 1202-11. doi: 10.3126/jpn.v7i2.18021 and melanomas. Dedifferentiation can arise de novo (combined with well differentiated tumor) at initial Copyright: This is an open-access article distributed under the terms of the Creative Commons diagnosis, or develop at recurrence or at metastatic site Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. and may follow therapy. A correct and early pathological identification of this phenomenon might profoundly help in guiding appropriate therapy. Clinical, radiological, immunohistochemistry and genetic analysis are often required for correct lineage identification of these tumors. This review will briefly highlight the mechanisms of tumor dedifferentiation in different types of malignant tumors, the DOI : 10.3126/jpn.v7i2.18021 Tumor dedifferentiation 1203 diagnostic dilemmas, and therapeutic implications. A pancreatic exocrine cell when reprogrammed with genes PDX1, NGN3 and MAFA can transdifferentiate into beta DIFFERENTIATION AND DEDIFFERENTIATION cell.5 Differentiation is a biological process by which a primitive Almost any differentiated cell can be reprogrammed to cell develop or evolutes into a mature cell within same pluripotent state by using appropriate transcription factors lineage to serve a specialized function. The conventional and many of them are oncogenes. This concept is also concept was that differentiation is unidirectional and once a applicable in phenomenon of origin of cancer stem cells. cell differentiates to mature cell type, it never reverts back, There are similarities between somatic reprogramming and like ball rolling down a hill into a landscape.4 A primitive tumor dedifferentiation.7 cell once becomes mature it never reverts back to stem cell again.4 This concept may not be applicable now as by CANCER STEM CELL AND INDUCED STEM artificial reprogramming process a mature cell can be sent CELLS back to stem cell state.4 In tissue regeneration a terminally differentiated cell reverts back to a less differentiated stage The process of dedifferentiation is involved in both initiation from within its own lineage to proliferate and re-differentiate and promotion of carcinogenesis.4 The phenomenon of again to replace the lost cells.5 reprogramming of somatic cells into iPSC is also a process of dedifferentiation, though it is induced experimentally.4 Dedifferentiation is a reprogramming process with iPSCs and cancer cells not only share the properties of morphological loss of lineage identity.6 The term is limitless replicative potential and self-renewal, but also applicable to a situation where a more specialized cell type shares similar metabolic status, that are acquired by loses expression of lineage specific genes of specialized somatic cells during reprogramming.4,12,13 Carcinogenesis tissue function and acquires expression of genes which is and reprogramming of somatic cells, both require similar seen in primitive state of the related tissue development.7,8 genetic alterations. This is also evident by the fact that iPSCs This genetic alteration in tumor cells results in acquisition generation is significantly promoted by genetic ablation of of stem cell phenotype.7,8 TP53 which is major tumor suppressor gene to be mutated in carcinogenesis.4,14,15 DIFFERENTIATION A BIDIRECTIONAL PROCESS The continuous growth and maintenance of many normal Biologists have successfully turned back the clock on cells, tissues such as skin, gastrointestinal epithelium and to convert the mature cells into pluripotent stem cells, hematopoietic cells in bone marrow depends on resident which can then differentiates into any cell lineage. This has population of stem cells that are capable of self renewal. been one of the most significant developments in field of With this background it easy to understand that cancer cells stem cell research.9 Nobel prize for 2012 in Medicine was are immortal and have limitless proliferative capacity, they awarded to Sir John B. Gurdon and Dr. Shinya Yamanka must contain cells that self-renew, the cancer stem cells.16 for the discovery that mature cells can be reprogrammed to Cancer stem cells (CSCs) are biologically unique cells become pluripotent cells.9 within a tumor, possessing self renewal capacity and produce progeny with self proliferative capacity, similar to normal The current experiment on induced stem cells (iPSC) has stem cells.7 Cancer stem cells can perpetuate indefinitely proved that differentiation of cells is bidirectional (fig.1).4 unlike bulk of cells that are present in the tumor.7 Cancer It is proven that a somatic nucleus can be reprogrammed stem cells is a cell that divides to replenish a population of to embryonic like state (pluripotency) by introducing cancer cells.17 four genes called Yamanaka factors (Oct 3/4, Sox2, Klf4, c-Myc).9-11 They are highly expressed in embryonic stem The concept of CSCs has important implications for cancer cells. Forced induction of these genes results in generation therapy. If CSCs are essential for persistence of cancer, of iPSC.10,11 A pluripotent cell can differentiate to any these cells must be eliminated to cure the cancer. Cancer lineage and give rise to different cell types. For example stem cells have high intrinsic resistance to conventional a pluripotent cell can differentiate to fibroblast, neuron, therapies due to low proliferative capacity and expression of exocrine cell of pancreas, beta cell of pancreas and multi drug resistance-1 (MDR1) that counteract the effects cardiac myocytes.5 A reprogramming process can induce a of chemotherapy. This is the reason for limited success in differentiated cell into pluripotent state which in other hand current cancer treatment due inability to eradicate Cancer can differentiate into any of cell types. For example mature stem cells.7,16 fibroblasts can be converted into pluripotent cells by the help of genes OCT4, SOX2, KLF4 and MYC. 5 Neural stem Cancer stem cells can arise from transformation of tissue cell can be reprogrammed to pluripotent stem cells by using stem cells or from conversion of conventional somatic gene OCT4. Cells can also change the lineage to another cell to transformed cells which acquire property of stem cell type and this phenomenon is called transdifferentiation. cells. Over that cancer cells within a tumor may be able to DOI : 10.3126/jpn.v7i2.18021 1204 Jha A et al. is the case in chronic phase of CML, however, in blast crisis dedifferentiation takes place and granulocyte-macrophage progenitor cells acquire stem cell like properties through beta catenin mutation.8,18,22 Many of the cancers show tumor cell plasticity.7 Plasticity is the potential of a differentiated cell to dedifferentiate back into a progenitor-like or stem-like state, and then to differentiate into a new differentiated state.17 This property of cancer cells has been demonstrated in glioblastoma by the works of Ronald de Pinho’s group and Figure 1: Pluripotent stem cell at the top (hill) and differentiated cells at Friedman-Morvinski D et al.23,24 Emergence and phenotype bottom (valley). The traditional concept of unidirectional differentiation (curved arrow on left). Current concept of bidirectional
Load more

Recommended publications
  • Ascl1a/Dkk/Β-Catenin Signaling Pathway Is Necessary and Glycogen Synthase Kinase-3Β Inhibition Is Sufficient for Zebrafish Retina Regeneration
    Ascl1a/Dkk/β-catenin signaling pathway is necessary and glycogen synthase kinase-3β inhibition is sufficient for zebrafish retina regeneration Rajesh Ramachandran, Xiao-Feng Zhao, and Daniel Goldman1 Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 Edited by David R. Hyde, University of Notre Dame, Notre Dame, IN, and accepted by the Editorial Board August 19, 2011 (received for review May 5, 2011) Key to successful retina regeneration in zebrafish are Müller glia necessary for proliferation of dedifferentiated MG in the injured (MG) that respond to retinal injury by dedifferentiating into a cy- retina and that glycogen synthase kinase-3β (GSK-3β) inhibition cling population of retinal progenitors. Although recent studies was sufficient to stimulate MG dedifferentiation into a pop- have identified several genes involved in retina regeneration, ulation of cycling multipotent progenitors in the uninjured ret- the signaling mechanisms underlying injury-dependent MG prolif- ina. Interestingly, Ascl1a knockdown limited the production of eration have remained elusive. Here we report that canonical Wnt neurons by progenitors in the GSK-3β inhibitor-treated retina. signaling controls the proliferation of MG-derived retinal progen- itors. We found that injury-dependent induction of Ascl1a sup- Results pressed expression of the Wnt signaling inhibitor, Dkk, and Ascl1a-Dependent Suppression of dkk Gene Expression in Injured induced expression of the Wnt ligand, Wnt4a. Genetic and phar- Retina. Wnt signaling is a conserved pathway that affects many macological inhibition of Wnt signaling suppressed injury-depen- fundamental developmental processes (18). Deregulated Wnt dent proliferation of MG-derived progenitors.
    [Show full text]
  • Dedifferentiation-Associated Changes in Morphology and Gene Expression in Primary Human Articular Chondrocytes in Cell Culture M
    Osteoarthritis and Cartilage (2002) 10, 62–70 © 2002 OsteoArthritis Research Society International 1063–4584/02/010062+09 $35.00/0 doi:10.1053/joca.2001.0482, available online at http://www.idealibrary.com on Dedifferentiation-associated changes in morphology and gene expression in primary human articular chondrocytes in cell culture M. Schnabel*, S. Marlovits†, G. Eckhoff*, I. Fichtel*, L. Gotzen*, V. Ve´csei† and J. Schlegel‡ *Department of Traumatology, Philipps-University of Marburg, Germany †Department of Traumatology, University of Vienna, Austria; Ludwig Boltzmann Institute of Biomechanics and Cell Biology, Vienna, Austria ‡Institute of Pathology, Munich Technical University, Germany Summary Objective: The aim of the present study was the investigation of differential gene expression in primary human articular chondrocytes (HACs) and in cultivated cells derived from HACs. Design: Primary human articular chondrocytes (HACs) isolated from non-arthritic human articular cartilage and monolayer cultures of HACs were investigated by immunohistochemistry, Northern analysis, RT-PCR and cDNA arrays. Results: By immunohistochemistry we detected expression of collagen II, protein S-100, chondroitin-4-sulphate and vimentin in freshly isolated HACs. Cultivated HACs, however, showed only collagen I and vimentin expression. These data were corroborated by the results of Northern analysis using specifc cDNA probes for collagens I, II and III and chondromodulin, respectively, demonstrating collagen II and chondromodulin expression in primary HACs but not in cultivated cells. Hybridization of mRNA from primary HACs and cultivated cells to cDNA arrays revealed additional transcriptional changes associated with dedifferentiation during propagation of chondrocytes in vitro.We found a more complex hybridization pattern for primary HACs than for cultivated cells.
    [Show full text]
  • Mouse Digit Tip Regeneration Is Mediated by Fate-Restricted Progenitor Cells
    Mouse digit tip regeneration is mediated by fate-restricted progenitor cells Jessica A. Lehoczkya, Benoît Robertb, and Clifford J. Tabina,1 aDepartment of Genetics, Harvard Medical School, Boston, MA 02115; and bInstitut Pasteur, Génétique Moléculaire de la Morphogenèse, Centre National de la Recherche Scientifique, Unité de Recherche Associée 2578, F-75015 Paris, France Contributed by Clifford J. Tabin, November 1, 2011 (sent for review September 19, 2011) Regeneration of appendages is frequent among invertebrates as tation of both the axolotl limb and the zebrafish fin strongly well as some vertebrates. However, in mammals this has been suggest that transdifferentiation does not significantly contribute largely relegated to digit tip regeneration, as found in mice and to the regenerates, and that instead the blastemas are made up of humans. The regenerated structures are formed from a mound of lineage-restricted cell populations (9–11). undifferentiated cells called a blastema, found just below the site Digit tip regeneration has been reported in mammals including of amputation. The blastema ultimately gives rise to all of the mice and juvenile humans (12, 13). Amputations of the terminal tissues in the regenerate, excluding the epidermis, and has classi- phalanx through levels associated with the nail organ are capable cally been thought of as a homogenous pool of pluripotent stem of regeneration, whereas more proximal amputations are not. cells derived by dedifferentiation of stump tissue, although this Intriguingly, mesenchymal nail bed cells in neonatal mice and has never been directly tested in the context of mammalian digit tip humans express the transcription factor Msx1 (14, 15), which is regeneration.
    [Show full text]
  • WNT Signaling in Lung Repair and Regeneration Ahmed A
    Molecules and Cells Minireview WNT Signaling in Lung Repair and Regeneration Ahmed A. Raslan1,2 and Jeong Kyo Yoon1,2,* 1Soonchunhyang Institute of Medi-bio Science and 2Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Korea *Correspondence: [email protected] https://doi.org/10.14348/molcells.2020.0059 www.molcells.org The lung has a vital function in gas exchange between the functions, the cellular composition and three-dimensional blood and the external atmosphere. It also has a critical structure of the lung must be maintained throughout an or- role in the immune defense against external pathogens ganism’s lifetime. Under normal conditions, the lung shows a and environmental factors. While the lung is classified as a low rate of cellular turnover relative to other organs, such as relatively quiescent organ with little homeostatic turnover, the skin and intestine, which exhibit rapid kinetics of cellular it shows robust regenerative capacity in response to injury, replacement characteristics (Bowden et al., 1968; Kauffman, mediated by the resident stem/progenitor cells. During 1980; Wansleeben et al., 2013). However, after injury or regeneration, regionally distinct epithelial cell populations with damage caused by different agents, including infection, toxic specific functions are generated from several different types compounds, and irradiation, the lung demonstrates a re- of stem/progenitor cells localized within four histologically markable ability to regenerate the damaged tissue (Hogan et distinguished regions: trachea, bronchi, bronchioles, and al., 2014; Lee and Rawlins, 2018; Wansleeben et al., 2013). alveoli. WNT signaling is one of the key signaling pathways If this regeneration process is not completed successfully, it involved in regulating many types of stem/progenitor cells leads to a disruption in proper lung function accompanied by in various organs.
    [Show full text]
  • Newly Identified Aspects of Tumor Suppression by RB
    Disease Models & Mechanisms 4, 581-585 (2011) doi:10.1242/dmm.008060 AT A GLANCE Newly identified aspects of tumor suppression by RB Patrick Viatour1,2,3 and Julien Sage1,2 The retinoblastoma (RB) tumor suppressor belongs to a interactions with E2F transcription factors (Chinnam and Goodrich, 2011; Knudsen and Knudsen, 2008). In this article and cellular pathway that plays a crucial role in restricting the the accompanying poster, we review recent evidence indicating that G1-S transition of the cell cycle in response to a large RB acts as a molecular adaptor at the crossroads of multiple number of extracellular and intracellular cues. Research pathways, depending on the cellular context. We also discuss the in the last decade has highlighted the complexity of idea that intact RB function might in some cases promote the early regulatory networks that ensure proper cell cycle steps of tumorigenesis, a provocative possibility for the first- progression, and has also identified multiple cellular identified tumor suppressor. functions beyond cell cycle regulation for RB and its two The RB pathway in cancer family members, p107 and p130. Here we review some Mutations targeting the RB pathway are almost universal in cancer, of the recent evidence pointing to a role of RB as a but different components of this pathway are selectively affected molecular adaptor at the crossroads of multiple in distinct cancer types (see ‘RB mutations in human cancers’ pathways, ensuring cellular homeostasis in different section of the poster). Events that affect upstream members of the contexts. In particular, we discuss the pro- and anti- pathway (e.g.
    [Show full text]
  • Dedifferentiation, Transdifferentiation, and Reprogramming: Future Directions in Regenerative Medicine
    82 Dedifferentiation, Transdifferentiation, and Reprogramming: Future Directions in Regenerative Medicine Cristina Eguizabal, PhD1 Nuria Montserrat, PhD1 Anna Veiga, PhD1,2 Juan Carlos Izpisua Belmonte, PhD1,3 1 Center for Regenerative Medicine in Barcelona Address for correspondence and reprint requests Juan Carlos Izpisua 2 Reproductive Medicine Service, Institut Universitari Dexeus, Belmonte, PhD, Gene Expression Laboratory, The Salk Institute for Barcelona, Spain Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 93027 3 Gene Expression Laboratory, The Salk Institute for Biological Studies, (e-mail: [email protected]). La Jolla, California Semin Reprod Med 2013;31:82–94 Abstract The main goal of regenerative medicine is to replace damaged tissue. To do this it is Keywords necessary to understand in detail the whole regeneration process including differenti- ► regenerative ated cells that can be converted into progenitor cells (dedifferentiation), cells that can medicine switch into another cell type (transdifferentiation), and somatic cells that can be ► stem cells induced to become pluripotent cells (reprogramming). By studying the regenerative ► dedifferentiation processes in both nonmammal and mammal models, natural or artificial processes ► transdifferentiation could underscore the molecular and cellular mechanisms behind these phenomena and ► reprogramming be used to create future regenerative strategies for humans. To understand any regenerative system, it is crucial to find the potency and differentiate and how they can revert to pluri- cellular origins of renewed tissues. Using techniques like potency (reprogramming) or switch lineages (dedifferentia- genetic lineage tracing and single-cell transplantation helps tion and transdifferentiation). to identify the route of regenerative sources. These tools were We synthesize the studies of different model systems to developed first in nonmammal models (flies, amphibians, and highlight recent insights that are integrating the field.
    [Show full text]
  • The Retinoblastoma Tumor Suppressor and Stem Cell Biology
    Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The retinoblastoma tumor suppressor and stem cell biology Julien Sage Department of Pediatrics, Department of Genetics, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Institute, Stanford, California 94305, USA Stem cells play a critical role during embryonic develop- control of small cell cycle inhibitors of the INK4 and ment and in the maintenance of homeostasis in adult CIP/KIP families, to which p16Ink4a and p21Cip1,respec- individuals. A better understanding of stem cell biology, tively, belong. The module comprising INK4–CIP/KIP including embryonic and adult stem cells, will allow the cell cycle inhibitors; Cyclin/Cdk complexes; RB and its scientific community to better comprehend a number of two family members, p107 and p130; and E2F transcrip- pathologies and possibly design novel approaches to treat tion factors constitutes the RB pathway in cells. A patients with a variety of diseases. The retinoblastoma second critical component of RB’s control of the G1/S tumor suppressor RB controls the proliferation, differenti- progression is nontranscriptional and connects RB to ation, and survival of cells, and accumulating evidence p27Kip1 stabilization via Cdh1/APC and Skp2. RB has points to a central role for RB activity in the biology of been shown to control many other cellular processes stem and progenitor cells. In some contexts, loss of RB in addition to cell cycle progression in G1, including function in stem or progenitor cells is a key event in the cellular differentiation, by functionally interacting with initiation of cancer and determines the subtype of cancer transcription factors important for the development of arising from these pluripotent cells by altering their fate.
    [Show full text]
  • Retinoblastoma Protein (RB) Interacts with E2F3 to Control Terminal Differentiation of Sertoli Cells E
    Retinoblastoma protein (RB) interacts with E2F3 to control terminal differentiation of Sertoli cells E. Rotgers, A. Rivero-Müller, M. Nurmio, M. Parvinen, Florian Jean Louis Guillou, I. Huhtaniemi, N. Kotaja, S. Bourguiba-Hachemi, J. Toppari To cite this version: E. Rotgers, A. Rivero-Müller, M. Nurmio, M. Parvinen, Florian Jean Louis Guillou, et al.. Retinoblas- toma protein (RB) interacts with E2F3 to control terminal differentiation of Sertoli cells. Cell Death and Disease, Nature Publishing Group, 2014, 5, pp.1-11. 10.1038/cddis.2014.232. hal-01129839 HAL Id: hal-01129839 https://hal.archives-ouvertes.fr/hal-01129839 Submitted on 27 May 2020 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. Citation: Cell Death and Disease (2014) 5, e1274; doi:10.1038/cddis.2014.232 OPEN & 2014 Macmillan Publishers Limited All rights reserved 2041-4889/14 www.nature.com/cddis Retinoblastoma protein (RB) interacts with E2F3 to control terminal differentiation of Sertoli cells E Rotgers1,2, A Rivero-Mu¨ller1, M Nurmio1,2, M Parvinen1, F Guillou3, I Huhtaniemi1,4, N Kotaja1, S Bourguiba-Hachemi1,5,6 and J Toppari*,1,2,6 The retinoblastoma protein (RB) is essential for normal cell cycle control.
    [Show full text]
  • Nanog: a Pluripotency Homeobox (Master) Molecule
    OPEN ACCESS Molecule of the month NaNog: A pluripotency homeobox (master) molecule Mona H. Allouba1, Ahmed M. ElGuindy1, Navaneethakrishnan Krishnamoorthy2,3, Magdi H. Yacoub1,2,3, Yasmine E. Aguib1,* 1Aswan Heart Centre, Aswan, Egypt 2Qatar Cardiovascular Research Centre, ABSTRACT Doha, Qatar 3Harefield Heart Science Centre, One of the most intriguing aspects of cell biology is the state of pluripotency, where the cell is capable National Heart and Lung Institute, of self-renewal for as many times as deemed “necessary”, then at a specified time can differentiate into Imperial College London, UK any type of cell. This fundamental process is required during organogenesis in foetal life and *Email: [email protected] importantly during tissue repair in health and disease. Pluripotency is very tightly regulated, as any dysregulation can result in congenital defects, inability to repair damage, or cancer. Fuelled by the relatively recent interest in stem cell biology and tissue regeneration, the molecules implicated in regulating pluripotency have been the subject of extensive research. One of the important molecules involved in pluripotency, is NaNog, the subject of this article. http://dx.doi.org/ 10.5339/gcsp.2015.36 Submitted: 29 April 2015 Accepted: 30 June 2015 ª 2015 Allouba, ElGuindy, Krishnamoorthy, Yacoub, Aguib, licensee Bloomsbury Qatar Foundation Journals. This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY 4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. Cite this article as: Allouba MH, ElGuindy AM, Krishnamoorthy N, Yacoub MH, Aguib YE. NaNog: A pluripotency homeobox (master) molecule, Global Cardiology Science and Practice 2015:36 http://dx.doi.org/10.5339/gcsp.2015.36 Page 2 of 9 Allouba et al.
    [Show full text]
  • Dedifferentiation Orchestrated Through Remodeling of the Chromatin Landscape Defines PSEN1 Mutation-Induced Alzheimer’S Disease
    bioRxiv preprint doi: https://doi.org/10.1101/531202; this version posted January 29, 2019. 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. Dedifferentiation orchestrated through remodeling of the chromatin landscape defines PSEN1 mutation-induced Alzheimer’s Disease Andrew B. Caldwell1, Qing Liu2, Gary P. Schroth3, Rudolph E. Tanzi4, Douglas R. Galasko2, Shauna H. Yuan2, Steven L. Wagner2,5, & Shankar Subramaniam1,6,7,8* 1Department of Bioengineering, University of California, San Diego, La Jolla, California, USA. 2Department of Neurosciences, University of California, San Diego, La Jolla, California, USA. 3Illumina, Inc., San Diego, California, USA. 4Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA. 5VA San Diego Healthcare System, La Jolla, California, USA. 6Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA. 7Department of Nanoengineering, University of California, San Diego, La Jolla, California, USA. 8Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California, USA. Abstract Early-Onset Familial Alzheimer’s Disease (EOFAD) is a dominantly inherited neurodegenerative disorder elicited by mutations in the PSEN1, PSEN2, and APP genes1. Hallmark pathological changes and symptoms observed, namely the accumulation of misfolded Amyloid-β (Aβ) in plaques and Tau aggregates in neurofibrillary tangles associated with memory loss and cognitive decline, are understood to be temporally accelerated manifestations of the more common sporadic Late-Onset Alzheimer’s Disease. The complete penetrance of EOFAD-causing mutations has allowed for experimental models which have proven integral to the overall understanding of AD2.
    [Show full text]
  • Transcription Factors Interfering with Dedifferentiation Induce Cell Type-Specific Transcriptional Profiles
    Transcription factors interfering with dedifferentiation induce cell type-specific transcriptional profiles Takafusa Hikichia,b, Ryo Matobac, Takashi Ikedaa,b, Akira Watanabeb, Takuya Yamamotob, Satoko Yoshitakea, Miwa Tamura-Nakanoa, Takayuki Kimuraa, Masayoshi Kamond, Mari Shimuraa, Koichi Kawakamie, Akihiko Okudad,f, Hitoshi Okochia, Takafumi Inoueg,1, Atsushi Suzukih,i,1, and Shinji Masuia,b,i,2 aResearch Institute, National Center for Global Health and Medicine, Tokyo 162-8655, Japan; bCenter for iPS Cell Research and Application, Kyoto University, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; cDNA Chip Research Inc., Suehirocho, Tsurumi-ku, Yokohama 230-0045, Japan; dResearch Center for Genomic Medicine, Saitama Medical University, Saitama 350-1241, Japan; eDivision of Molecular and Developmental Biology, National Institute of Genetics, Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), Mishima, Shizuoka 411-8540, Japan; fCREST (Core Research for Evolutional Science and Technology), Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan; gDepartment of Life Science and Medical Bioscience, Waseda University, Shinjuku-ku, Tokyo 162-8480, Japan; hDivision of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan; and iPRESTO (Precursory Research for Embryonic Science and Technology), Japan Science and Technology Agency, Saitama 332-0012, Japan Edited* by Shinya Yamanaka, Kyoto University, Kyoto, Japan, and approved March 5, 2013 (received for review November 27, 2012) Transcription factors (TFs) are able to regulate differentiation- respective cell type-specific transcriptional profile. Supporting related processes, including dedifferentiation and direct conversion, evidence in B lymphocytes has indicated the repression of iPSC through the regulation of cell type-specific transcriptional profiles. induction by paired box gene 5 (Pax5, a core TF) (8).
    [Show full text]
  • Dynamic Regulation of Nanog and Stem Cell-Signaling Pathways by Hoxa1 During Early Neuro-Ectodermal Differentiation of ES Cells
    Dynamic regulation of Nanog and stem cell-signaling pathways by Hoxa1 during early neuro-ectodermal differentiation of ES cells Bony De Kumara, Hugo J. Parkera, Mark E. Parrisha, Jeffrey J. Langea, Brian D. Slaughtera, Jay R. Unruha, Ariel Paulsona, and Robb Krumlaufa,b,1 aStowers Institute for Medical Research, Kansas City, MO 64110; and bDepartment of Anatomy and Cell Biology, Kansas University Medical Center, Kansas City, KS 66160 Edited by Ellen V. Rothenberg, California Institute of Technology, Pasadena, CA, and accepted by Editorial Board Member Neil H. Shubin October 24, 2016 (received for review July 28, 2016) Homeobox a1 (Hoxa1) is one of the most rapidly induced genes in also feed into this GRN to maintain cells in a pluripotency state ES cell differentiation and it is the earliest expressed Hox gene in the by modulating expression of core network components (8–11). mouse embryo. In this study, we used genomic approaches to iden- The expression of the core pluripotency network involves the ex- tify Hoxa1-bound regions during early stages of ES cell differentia- tensive deployment of auto- and cross-regulatory feedback inter- tion into the neuro-ectoderm. Within 2 h of retinoic acid treatment, actions. For example, Nanog is known to directly activate Oct4 and Hoxa1 is rapidly recruited to target sites that are associated with Sox2, whereas they in turn positively cross-regulate Nanog. Oct4 genes involved in regulation of pluripotency, and these genes dis- and Sox2 positively feedback to maintain their own expression via play early changes in expression. The pattern of occupancy of Hoxa1 direct autoregulation, whereas Nanog modulates its level of gene is dynamic and changes over time.
    [Show full text]