DOCSLIB.ORG

The Role of Androgens and Androgen Receptor in Human Bladder Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Role of Androgens and Androgen Receptor in Human Bladder Cancer biomolecules Review The Role of Androgens and Androgen Receptor in Human Bladder Cancer Elizabeth Martínez-Rojo, Laura Cristina Berumen , Guadalupe García-Alcocer and Jesica Escobar-Cabrera * Unidad de Investigación Genética, Posgrado en Ciencias Químico Biológicas, Facultad de Química, Universidad Autónoma de Querétaro, Querétaro 76010, Mexico; [email protected] (E.M.-R.); [email protected] (L.C.B.); [email protected] (G.G.-A.) * Correspondence: [email protected]; Tel.: +55-4421287051 Abstract: Bladder cancer (urothelial carcinoma) is one of the most frequently diagnosed neoplasms, with an estimated half a million new cases and 200,000 deaths per year worldwide. This pathol- ogy mainly affects men. Men have a higher risk (4:1) of developing bladder cancer than women. Cigarette smoking and exposure to chemicals such as aromatic amines, and aniline dyes have been established as risk factors for bladder cancer and may contribute to the sex disparity. Male internal genitalia, including the urothelium and prostate, are derived from urothelial sinus endoderm; both tissues express the androgen receptor (AR). Several investigations have shown evidence that the AR plays an important role in the initiation and development of different types of cancer including bladder cancer. In this article, we summarize the available data that help to explain the role of the AR in the development and progression of bladder cancer, as well as the therapies used for its treatment. Keywords: androgens; androgen receptor; bladder cancer; signaling pathways; therapies Citation: Martínez-Rojo, E.; Berumen, L.C.; García-Alcocer, G.; Escobar-Cabrera, J. The Role of 1. Introduction Androgens and Androgen Receptor Bladder cancer has high incidence and mortality around the world. Approximately, in Human Bladder Cancer. half a million new cases and 200,000 deaths have been reported worldwide per year [1]. Biomolecules 2021, 11, 594. https:// In the United States, it is the fourth leading cause of death in men. About 83,730 new cases doi.org/10.3390/biom11040594 and 17,200 deaths from this pathology among men and women have been estimated [2]. Most of the people affected by this pathology are men over 65 years of age and, to a Academic Editor: Alessandro Alaimo lesser extent, women. The main risk factors are smoking, exposure to chemicals, radiation therapy, and chemotherapy [3]. Androgens are classically known for their role in the male Received: 1 March 2021 reproductive system. Androgens and their receptors control the transcription of genes Accepted: 15 April 2021 Published: 18 April 2021 associated with processes such as cell cycle, survival, and differentiation; thus, the study of their influence on the development, progression, and diagnosis in different types of cancer is very important [4]. Different studies have shown that the presence of androgens and Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in their receptor is strongly associated with bladder cancer [5]. published maps and institutional affil- The aim of this review is to collect the most recent information on the role of androgens iations. and the AR in the development and progression of bladder cancer, as well as the signaling pathways involved and new therapies. 2. Structure of Androgens and Androgen Receptors Androgens are a group of steroid hormones that include mainly testosterone, which is Copyright: © 2021 by the authors. α Licensee MDPI, Basel, Switzerland. converted to 5 -dihydrotestosterone (DHT, its active metabolite which shows a 2–5 times This article is an open access article higher binding affinity to the AR than that of testosterone) through the action of the en- distributed under the terms and zyme 5α-reductase [4]. Androgens are produced from the transformation of cholesterol conditions of the Creative Commons in the testes (Leydig cells), ovaries, adrenal gland [4,6] muscles, fat tissue, skin, and en- Attribution (CC BY) license (https:// dometrium [7]. creativecommons.org/licenses/by/ The AR belongs to the steroid receptor family (NR3C4 of the 3-ketosteroid receptors, 4.0/). family III), one of the subtypes of the nuclear receptor superfamily, the latter composed Biomolecules 2021, 11, 594. https://doi.org/10.3390/biom11040594 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x 2 of 16 in the testes (Leydig cells), ovaries, adrenal gland [4,6] muscles, fat tissue, skin, and endo- Biomolecules 2021, 11metrium, 594 [7]. 2 of 16 The AR belongs to the steroid receptor family (NR3C4 of the 3-ketosteroid receptors, family III), one of the subtypes of the nuclear receptor superfamily, the latter composed of more than 500 transcription factors modulating gene expression [8–10]. The AR is com- of more than 500 transcription factors modulating gene expression [8–10]. The AR is posed of four different domains; an N-terminal domain (NTD), which contains the activa- composed of four different domains; an N-terminal domain (NTD), which contains the tion function-1 (AF-1) domain, which contains essential sites of phosphorylation; a DNA- activation function-1 (AF-1) domain, which contains essential sites of phosphorylation; a binding domain (DBD) that has two zinc fingers, and its function is the recognition, di- DNA-binding domain (DBD) that has two zinc fingers, and its function is the recognition, merization, and binding to the DNA in androgen responsive elements (ARE); a hinge, a dimerization, and binding to the DNA in androgen responsive elements (ARE); a hinge, a lysine rich region that is important for nuclear receptor localization; and a ligand-binding lysine rich region that is important for nuclear receptor localization; and a ligand-binding domain (LBD) that contains the AF-2 [6,11]. The AR gene is located on the long arm of the domain (LBD) that contains the AF-2 [6,11]. The AR gene is located on the long arm of the X-chromosomeX-chromosome and is expressed and in is several expressed tissues in several, including tissues, the includingprostate, breast, the prostate, testes, breast, testes, skeletal muscle,skeletal uterus muscle,, and bladder uterus, [11]. and The bladder AR belongs [11]. The to AR the belongs family of to transcription the family of transcription factors that homodimerizefactors that homodimerize after ligand-binding, after ligand-binding, while RXR receptors while RXR may receptors heterodimer- may heterodimerize, ize, and monomericand monomeric orphan receptors orphan do receptors not require do not dimerization require dimerization [12,13]. [12,13]. 3. Activation of3. Androgen Activation Receptor of Androgen and ReceptorCofactorsand Cofactors In the absenceIn of the a ligand, absence the of AR a ligand, is bound the to AR heat is bound shock toproteins heat shock that prevent proteins the that prevent the translocation totranslocation the nucleus to and the protect nucleus the and receptors protect thefrom receptors degradation from (and degradation from the (and from the generation of toxicgeneration AR aggregates) of toxic AR and aggregates) remains in the and cytoplasm; remains in after the ligand cytoplasm; binding, after the ligand binding, AR dissociatesthe from AR the dissociates heat shock from proteins the heat and shock transloc proteinsates and to the translocates nucleus. toIn thethe nucleus. nu- In the nu- cleus, the AR bindscleus, to the ARE AR located binds to on ARE the DNA located promoter on the DNA via zinc promoter finger viabinding zinc fingerdomains. binding domains. Once the AR dimerOnce theis bound AR dimer to the is boundDNA, it to forms the DNA, complexes it forms with complexes transcriptional with transcriptional coacti- coactiva- vators and co-regulatorstors and co-regulators for the regulation for the of regulation target gene of expression target gene (Figure expression 1) [4,6,14 (Figure–18].1)[ 4,6,14–18]. Figure 1. Genomic androgenFigure receptor 1. Genomic pathway androgen. receptor pathway. Coregulators areCoregulators not DNA- arebinding not DNA-binding proteins, but proteins, are recruited but are to recruitedtranscription to transcription fac- factors, tors, such as thesuch AR, as and the have AR, anddifferent have differentactivities activitiesinvolved involvedin the regulation in the regulation of gene ex- of gene expres- pression; somesion; of them some cause of them chromatin cause reconfiguration chromatin reconfiguration or are needed or to are bind needed some toother bind some other cofactors [19]. cofactors [19]. Liu et al., 2017Liu studied et al., the 2017 AR studiedcoregulators the ARin association coregulators with in prostate association cancer; with they prostate cancer; worked with 181they coregulators worked with interacting 181 coregulators physically interacting and functionally physically, with and ARfunctionally, 51 of them with AR 51 associated withof prostate them associated cancer and with 22 prostatecorrelated cancer with andthe most 22 correlated aggressive with characteristics the most aggressive char- (Figure 2). Theyacteristics managed (Figure the knockout2). They of managed the 22 coregulators the knockout and of identified the 22 coregulators four of them and identified that decreasedfour AR ofprotein them thatexpression decreased (GAK, AR proteinHIP1, RAD9A expression, and (GAK, SMAD3). HIP1, They RAD9A, con- and SMAD3). firmed the participationThey confirmed of the the other participation 18 coregulators of the other, silencing 18 coregulators, each factor silencing individually each factor individ- with specific siRNuallyA, with with
Load more

Recommended publications
  • Manual: Pathdetect Reporter Cell Lines
    PathDetect Reporter Cell Lines INSTRUCTION MANUAL Catalog #800050 (PathDetect HLR Cell Line) #800055 (HLR-Elk1 Cell Line) #800060 (HLR-CHOP Cell Line) #800065 (HLR-CREB Cell Line) Revision A BN #800050-12 For In Vitro Use Only 800050-12 LIMITED PRODUCT WARRANTY This warranty limits our liability to replacement of this product. No other warranties of any kind, express or implied, including without limitation, implied warranties of merchantability or fitness for a particular purpose, are provided by Agilent. Agilent shall have no liability for any direct, indirect, consequential, or incidental damages arising out of the use, the results of use, or the inability to use this product. ORDERING INFORMATION AND TECHNICAL SERVICES United States and Canada Agilent Technologies Stratagene Products Division 11011 North Torrey Pines Road La Jolla, CA 92037 Telephone (858) 373-6300 Order Toll Free (800) 424-5444 Technical Services (800) 894-1304 Internet [email protected] World Wide Web www.stratagene.com Europe Location Telephone Fax Technical Services Austria 0800 292 499 0800 292 496 0800 292 498 Belgium 00800 7000 7000 00800 7001 7001 00800 7400 7400 0800 15775 0800 15740 0800 15720 France 00800 7000 7000 00800 7001 7001 00800 7400 7400 0800 919 288 0800 919 287 0800 919 289 Germany 00800 7000 7000 00800 7001 7001 00800 7400 7400 0800 182 8232 0800 182 8231 0800 182 8234 Netherlands 00800 7000 7000 00800 7001 7001 00800 7400 7400 0800 023 0446 +31 (0)20 312 5700 0800 023 0448 Switzerland 00800 7000 7000 00800 7001 7001 00800 7400 7400 0800 563 080 0800 563 082 0800 563 081 United Kingdom 00800 7000 7000 00800 7001 7001 00800 7400 7400 0800 917 3282 0800 917 3283 0800 917 3281 All Other Countries Please contact your local distributor.
    [Show full text]
  • Expression of Oncogenes ELK1 and ELK3 in Cancer
    Review Article Annals of Colorectal Cancer Research Published: 11 Nov, 2019 Expression of Oncogenes ELK1 and ELK3 in Cancer Akhlaq Ahmad and Asif Hayat* College of Chemistry, Fuzhou University, China Abstract Cancer is the uncontrolled growth of abnormal cells anywhere in a body, ELK1 and ELK3 is a member of the Ets-domain transcription factor family and the TCF (Ternary Complex Factor) subfamily. Proteins in this subfamily regulate transcription when recruited by SRF (Serum Response Factor) to bind to serum response elements. ELK1 and ELK3 transcription factors are known as oncogenes. Both transcription factors are proliferated in a different of type of cancer. Herein, we summarized the expression of transcription factor ELK1 and ELK3 in cancer cells. Keywords: ETS; ELK1; ELK3; Transcription factor; Cancer Introduction The ETS, a transcription factor of E twenty-six family based on a dominant ETS amino acids that integrated with a ~10-basepair element arrange in highly mid core sequence 5′-GGA(A/T)-3′ [1-2]. The secular family alter enormous 28/29 members which has been assigned in human and mouse and similarly the family description are further sub-divided into nine sub-families according to their homology and domain factor [3]. More importantly, one of the subfamily members such as ELK (ETS-like) adequate an N-terminal ETS DNA-binding domain along with a B-box domain that transmit the response of serum factor upon the formation of ternary complex and therefore manifested as ternary complex factors [4]. Further the ELK sub-divided into Elk1, Elk3 (Net, Erp or Sap2) and Elk4 (Sap1) proteins [3,4], which simulated varied proportional of potential protein- protein interactions [4,5].
    [Show full text]
  • New Mechanism Based Approaches for Treating Prostate Cancer Rayna Rosati Wayne State University
    Wayne State University Wayne State University Dissertations 1-1-2017 New Mechanism Based Approaches For Treating Prostate Cancer Rayna Rosati Wayne State University, Follow this and additional works at: https://digitalcommons.wayne.edu/oa_dissertations Part of the Oncology Commons Recommended Citation Rosati, Rayna, "New Mechanism Based Approaches For Treating Prostate Cancer" (2017). Wayne State University Dissertations. 1865. https://digitalcommons.wayne.edu/oa_dissertations/1865 This Open Access Dissertation is brought to you for free and open access by DigitalCommons@WayneState. It has been accepted for inclusion in Wayne State University Dissertations by an authorized administrator of DigitalCommons@WayneState. NEW MECHANISM BASED APPROACHES FOR TREATING PROSTATE CANCER by RAYNA C. ROSATI DISSERTATION Submitted to the Graduate School of Wayne State University, Detroit, Michigan in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY 2017 MAJOR: CANCER BIOLOGY Approved By: Advisor Date DEDICATION This dissertation is dedicated to my family, who made me who I am today with all of their love and support. To my grandmother, Lucy, who just recently lost her battle with lung cancer and who would send me newspaper clippings in the mail about new topics of prostate cancer research. To my siblings, who have always been my best friends. To my father, Daniel, who has been my greatest mentor in life. To my mother, Nanci, who has been there for me through everything and who gave me my creative bone. ii ACKNOWLEDGEMENTS First off, I would like to thank my mentor, Dr. Manohar Ratnam, whose enthusiasm for science is undeniable. Thank you for always being so optimistic and believing I could accomplish this very challenging project.
    [Show full text]
  • Modulation of Transcriptional Activity in Brain Lower Grade Glioma by Alternative Splicing
    A peer-reviewed version of this preprint was published in PeerJ on 14 May 2018. View the peer-reviewed version (peerj.com/articles/4686), which is the preferred citable publication unless you specifically need to cite this preprint. Li J, Wang Y, Meng X, Liang H. 2018. Modulation of transcriptional activity in brain lower grade glioma by alternative splicing. PeerJ 6:e4686 https://doi.org/10.7717/peerj.4686 Modulation of transcriptional activity in brain lower grade glioma by alternative splicing Jin Li 1 , Yang Wang 1 , Xianglian Meng 1 , Hong Liang Corresp. 1 1 College of Automation, Harbin Engineering University, Harbin, Heilongjiang, China Corresponding Author: Hong Liang Email address: [email protected] Proteins that modify the activity of transcription factor (TF), often called modulators, play a vital role in gene transcriptional regulation. Alternative splicing is a critical step of gene processing and it can modulate gene function by adding or removing certain protein domains, and therefore influences the activity of a protein. The objective of this study is to investigate the role of alternative splicing in modulating the transcriptional regulation in brain lower grade glioma (LGG), especially transcription factor ELK1, which is closely related to various diseases, including Alzheimer’s disease and down syndrome. Results showed that changes in the exon inclusion ratio of proteins APP and STK16 are associated with changes in the expression correlation between ELK1 and its targets. Meanwhile, the structural features of the two modulators are strongly associated with the pathological impact of exon inclusion. Our analysis suggests, protein in different splicing level could play different functions on transcription factors, hence induces multiple genes dysregulation.
    [Show full text]
  • Investigating the Role of the ETS Transcription Factor ELK1 in Stem Cell Transcription
    Investigating the role of the ETS transcription factor ELK1 in stem cell transcription A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Biology, Medicine and Health 2017 Ian E. Prise Division of Molecular & Cellular Function School of Biological Sciences I. Table of Contents II. List of Figures ...................................................................................................................................... 5 III. Abstract .............................................................................................................................................. 7 IV. Declaration ......................................................................................................................................... 8 V. Copyright Statement ........................................................................................................................... 8 VI. Experimental Contributions ............................................................................................................... 9 VII. Acknowledgments .......................................................................................................................... 10 1. Introduction ...................................................................................................................................... 12 1.I Pluripotency ................................................................................................................................. 12 1.II Chromatin
    [Show full text]
  • MEKK1/JNK Signaling Stabilizes and Activates P53
    Proc. Natl. Acad. Sci. USA Vol. 95, pp. 10541–10546, September 1998 Biochemistry MEKK1/JNK signaling stabilizes and activates p53 SERGE Y. FUCHS*, VICTOR ADLER*, MATTHEW R. PINCUS†, AND ZE’EV RONAI*‡ *Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY 10029; and †Department of Pathology and Laboratory Medicine, Brooklyn Veterans Affairs Medical Center and State University of New York Health Science, Brooklyn, NY 11203 Communicated by H. A. Scheraga, Cornell University, Ithaca, NY, July 7, 1998 (received for review May 4, 1998) ABSTRACT Activation of the tumor suppressor p53 by damage is preserved in cells from severe combined immunode- stress and damage stimuli often correlates with induction of ficient mice (10–12), we examined the role of JNK in this stress kinases, Jun-NH2 kinase (JNK). As JNK association response. with p53 plays an important role in p53 stability, in the JNKs are a family of stress kinases induced by change in redox present study we have elucidated the relationship between the potential, heat shock, osmotic shock, UV irradiation, and inflam- JNK-signaling pathway and p53 stability and activity. Expres- matory cytokines (13–16). JNK activity requires mitogen- sion of a constitutively active form of JNKK upstream kinase, activated protein kinases kinase (MEKK) 1–4 which phosphor- mitogen-activated protein kinase kinase kinase (DMEKK1), ylates MKK4/7. MKK4/7, in turn, phosphorylates JNK on resi- increased the level of the exogenously transfected form of p53 dues 183 and 185 (17–20). Activated JNK phosphorylates its in p53 null (10.1) cells as well as of endogenous p53 in MCF7 substrates, c-Jun, ATF2, ELK1, and p53 (3, 13–14, 21).
    [Show full text]
  • The Structure-Function Relationship of Angular Estrogens and Estrogen Receptor Alpha to Initiate Estrogen-Induced Apoptosis in Breast Cancer Cells S
    Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2020/05/03/mol.120.119776.DC1 1521-0111/98/1/24–37$35.00 https://doi.org/10.1124/mol.120.119776 MOLECULAR PHARMACOLOGY Mol Pharmacol 98:24–37, July 2020 Copyright ª 2020 The Author(s) This is an open access article distributed under the CC BY Attribution 4.0 International license. The Structure-Function Relationship of Angular Estrogens and Estrogen Receptor Alpha to Initiate Estrogen-Induced Apoptosis in Breast Cancer Cells s Philipp Y. Maximov, Balkees Abderrahman, Yousef M. Hawsawi, Yue Chen, Charles E. Foulds, Antrix Jain, Anna Malovannaya, Ping Fan, Ramona F. Curpan, Ross Han, Sean W. Fanning, Bradley M. Broom, Daniela M. Quintana Rincon, Jeffery A. Greenland, Geoffrey L. Greene, and V. Craig Jordan Downloaded from Departments of Breast Medical Oncology (P.Y.M., B.A., P.F., D.M.Q.R., J.A.G., V.C.J.) and Computational Biology and Bioinformatics (B.M.B.), University of Texas, MD Anderson Cancer Center, Houston, Texas; King Faisal Specialist Hospital and Research (Gen.Org.), Research Center, Jeddah, Kingdom of Saudi Arabia (Y.M.H.); The Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois (R.H., S.W.F., G.L.G.); Center for Precision Environmental Health and Department of Molecular and Cellular Biology (C.E.F.), Mass Spectrometry Proteomics Core (A.J., A.M.), Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Mass Spectrometry Proteomics Core (A.M.), and Dan L. Duncan molpharm.aspetjournals.org
    [Show full text]
  • GATA3 Acts Upstream of FOXA1 in Mediating ESR1 Binding by Shaping Enhancer Accessibility
    Downloaded from genome.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Research GATA3 acts upstream of FOXA1 in mediating ESR1 binding by shaping enhancer accessibility Vasiliki Theodorou,1 Rory Stark,2 Suraj Menon,2 and Jason S. Carroll1,3,4 1Nuclear Receptor Transcription Lab, 2Bioinformatics Core, Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, United Kingdom; 3Department of Oncology, University of Cambridge, Cambridge CB2 OXZ, United Kingdom Estrogen receptor (ESR1) drives growth in the majority of human breast cancers by binding to regulatory elements and inducing transcription events that promote tumor growth. Differences in enhancer occupancy by ESR1 contribute to the diverse expression profiles and clinical outcome observed in breast cancer patients. GATA3 is an ESR1-cooperating transcription factor mutated in breast tumors; however, its genomic properties are not fully defined. In order to investigate the composition of enhancers involved in estrogen-induced transcription and the potential role of GATA3, we performed extensive ChIP-sequencing in unstimulated breast cancer cells and following estrogen treatment. We find that GATA3 is pivotal in mediating enhancer accessibility at regulatory regions involved in ESR1-mediated transcription. GATA3 silencing resulted in a global redistribution of cofactors and active histone marks prior to estrogen stimulation. These global genomic changes altered the ESR1-binding profile that subsequently occurred following estrogen, with events exhibiting both loss and gain in binding affinity, implying a GATA3-mediated redistribution of ESR1 binding. The GATA3-mediated redistributed ESR1 profile correlated with changes in gene expression, suggestive of its functionality. Chromatin loops at the TFF locus involving ESR1-bound enhancers occurred independently of ESR1 when GATA3 was silenced, indicating that GATA3, when present on the chromatin, may serve as a licensing factor for estrogen–ESR1-mediated interactions between cis-regulatory elements.
    [Show full text]
  • 1 Loss of ELK1 Has Differential Effects on Age-Dependent Organ Fibrosis
    bioRxiv preprint doi: https://doi.org/10.1101/755694; this version posted September 5, 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. Loss of ELK1 has differential effects on age-dependent organ fibrosis and integrin expression Running title Aged, ELK1 deficient mice develop fibrosis and altered integrin expression Jennifer T Cairns1, Anthony Habgood1, Rochelle C Edwards-Pritchard1, Chloe Wilkinson1, Iain D Stewart1, Jack Leslie2, Burns C Blaxall3, Katalin Susztak4, Siegfried Alberti5, Alfred Nordheim5, Fiona Oakley2, R Gisli Jenkins1, Amanda L Tatler1. 1 Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham, NG5 1PB, UK and Respiratory Research Unit, NIHR Biomedical Research Centre, Nottingham University Hospitals Nottingham, UK. 2 Newcastle Fibrosis Research Group, Institute of Cellular Medicine, Faculty of Medical Sciences, 4th Floor, William Leech Building, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK 3 Department of Precision Medicine and Pharmacogenetics, The Christ Hospital Health Network, Cincinnati, Ohio, USA 4 Renal Electrolyte and Hypertension Division, Department of Medicine, Department of Genetics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA 5 Interfaculty Institute of Cell Biology, Tuebingen University, Germany and 6 Leibniz Institute on Aging (FLI), Jena, Germany 1 bioRxiv preprint doi: https://doi.org/10.1101/755694; this version posted September 5, 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.
    [Show full text]
  • TDP-43 Regulates Retinoblastoma Protein Phosphorylation Through the Repression of Cyclin-Dependent Kinase 6 Expression
    TDP-43 regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 expression Youhna M. Ayala*, Tom Misteli†, and Francisco E. Baralle*‡ *International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy; and †Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, 41 Library Drive, Building 41, Bethesda, MD 20892 Communicated by Jorge E. Allende, University of Chile, Santiago, Chile, January 21, 2008 (received for review September 3, 2007) TDP-43 (for TAR DNA binding protein) is a highly conserved we found that TDP-43 silencing alters cell cycle distribution and heterogeneous nuclear ribonucleoprotein (hnRNP) involved in spe- induces apoptosis. cific pre-mRNA splicing and transcription events. TDP-43 recently has been identified as the main component of cytoplasmic inclu- Results sions in frontotemporal lobar degeneration (FTLD) and amyotro- TDP-43 Down-Regulation Alters the Expression of pRb-Related Fac- phic lateral sclerosis (ALS), two neurodegenerative disorders. The tors. TDP-43 was depleted from HeLa cells by RNAi routinely cellular role of this protein remains to be identified. Here, we show achieving Ͼ90% silencing as measured by Western blot, 48 h that loss of TDP-43 results in dysmorphic nuclear shape, misregu- after small interfering RNA (siRNA) transfection (3, 5). RNA lation of the cell cycle, and apoptosis. Removal of TDP-43 in human microarray analysis was performed on TDP-43 depleted and cells significantly increases cyclin-dependent kinase 6 (Cdk6) pro- control treated cells. The data obtained indicated altered levels tein and transcript levels. The control of Cdk6 expression mediated of several cell proliferation factors in TDP-43-silenced cells.
    [Show full text]
  • Genome-Wide Crosstalk Between Steroid Receptors in Breast and Prostate Cancers
    28 9 Endocrine-Related V Paakinaho and J J Palvimo Steroid receptor crosstalk in 28:9 R231–R250 Cancer cancers REVIEW Genome-wide crosstalk between steroid receptors in breast and prostate cancers Ville Paakinaho and Jorma J Palvimo Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland Correspondence should be addressed to J J Palvimo: [email protected] Abstract Steroid receptors (SRs) constitute an important class of signal-dependent transcription Key Words factors (TFs). They regulate a variety of key biological processes and are crucial drug f androgen receptor targets in many disease states. In particular, estrogen (ER) and androgen receptors (AR) f estrogen receptor drive the development and progression of breast and prostate cancer, respectively. f glucocorticoid receptor Thus, they represent the main specific drug targets in these diseases. Recent evidence f progesterone receptor has suggested that the crosstalk between signal-dependent TFs is an important step f breast cancer in the reprogramming of chromatin sites; a signal-activated TF can expand or restrict f prostate cancer the chromatin binding of another TF. This crosstalk can rewire gene programs and thus f chromatin alter biological processes and influence the progression of disease. Lately, it has been f crosstalk postulated that there may be an important crosstalk between the AR and the ER with other SRs. Especially, progesterone (PR) and glucocorticoid receptor (GR) can reprogram chromatin binding of ER and gene programs in breast cancer cells. Furthermore, GR can take the place of AR in antiandrogen-resistant prostate cancer cells. Here, we review the current knowledge of the crosstalk between SRs in breast and prostate cancers.
    [Show full text]
  • PPM1G Promotes the Progression of Hepatocellular Carcinoma Via
    www.nature.com/cddis ARTICLE OPEN PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3 ✉ ✉ Dawei Chen1, Zhenguo Zhao1, Lu Chen1, Qinghua Li1, Jixue Zou 2 and Shuanghai Liu 1 © The Author(s) 2021 Emerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation. Cell Death and Disease (2021) 12:722 ; https://doi.org/10.1038/s41419-021-04013-y INTRODUCTION The AR-V7 is specifically highly expressed in patients with relapse Hepatocellular carcinoma (HCC) is one of the most aggressive and drug resistance after targeted therapy.
    [Show full text]