DOCSLIB.ORG

Deconstructing Myc

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Deconstructing Myc Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Deconstructing Myc Robert N. Eisenman1 Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA Background Max, determines cell behavior by activation of a specific set of target genes. However, on second glance a number Although myc was among the very earliest oncogenes of complicating issues arise. First, Myc–Max transcrip- identified and the subject of intense study, it has none- tional activity on either synthetic promoters or putative theless proven to be an enduring enigma. To a large ex- cellular target genes is disappointingly weak and variable tent the problem derives from the apparent gap between (compared with other activators)—on the order of 2–5 Myc’s biological role and what is surmised to be its mo- fold. This makes detailed dissection of transcriptional lecular function. Myc family proteins (comprising c-, N-, function difficult and, even worse, makes validation of and L-Myc) promote proliferation, growth, and apopto- putative target genes both awkward and contentious (for sis; inhibit terminal differentiation; and, when deregu- review, see Grandori and Eisenman 1997). Second, al- lated, are profoundly involved in the genesis of an ex- though the transcriptional activity of Myc–Max was traordinarily wide range of cancers (for recent review, see widely confirmed, there were also reports that Myc Grandori et al. 2000). Alongside this veritable mountain could repress transcription of a number of genes depen- of biological effects, the molecular characterization of dent on a specific subclass of initiator elements (INRs) Myc—as a relatively weak transcriptional regulator of located at the transcriptional initiation sites of certain uncertain target genes—looks like a molehill. Indeed genes (Li et al. 1994). Because the repression experiments some have wondered whether the transcriptional activi- did not demonstrate Myc binding to INRs, they left open ties of Myc might be more apparent than real. the possibility that repression might be indirect (e.g. The notion that Myc proteins might function in tran- through activation of a repressor by Myc–Max). Third, scription arose over a decade ago, after Myc was shown mutational analyses of Myc Box II, a highly conserved to be a nuclear protein. An N-terminal fragment of Myc region present in the N-terminal transactivation region stimulated transcription when fused to a heterologous of all Myc proteins, produced confounding results. Sev- DNA binding domain, and the C-terminal basic-helix- eral reports indicated that mutation of Myc Box II had loop-helix-zipper (bHLHZ) of Myc resembled those little effect on transcription activation but abrogated found in certain families of transcription factors. But Myc repression activity. Yet other studies indicated that full-length Myc did not dimerize or bind DNA and there- loss of Myc Box II primarily affected activation. Because fore could not be demonstrated to behave as a transcrip- Myc Box II is crucial for the ability of Myc to transform tion factor. This picture changed with the discovery of cells, these results raised the issue of the relative impor- Max, another bHLHZ protein which heterodimerizes tance of activation and repression (for review, see Gran- with Myc to form a sequence-specific DNA binding dori et al. 2000). complex. Myc–Max heterodimers recognize the E-box In principle, the importance of Myc transcriptional ac- sequence CACGTG (as well as related non-canonical tivity could be settled by identification of specific target sites) and activate transcription from synthetic reporter genes. The hope was that Myc–Max might modulate ex- genes containing multimerized binding sites in mamma- pression of a small number of obviously critical genes lian cells as well as yeast (Blackwood and Eisenman whose known functions would explain the various bio- 1991; Amati et al. 1992; Kretzner et al. 1992). The effects logical effects of Myc. However, over the last eight years of Myc on cell proliferation and apoptosis are negated by numerous putative target genes have been identified and, mutations in the Myc transactivation region, or in the with the advent of global expression arrays, the number bHLHZ domain required for association with Max and that are activated or repressed by Myc continues to grow. DNA, indicating a tight linkage between the transcrip- Whereas a few of these targets are cell cycle regulators, tional and biological activities of Myc. and therefore might help explain the ability of Myc to At first glance these findings would be expected to drive proliferation, many other candidate target genes settle the issue of Myc function in favor of the idea that have functions relating to metabolism, ribosome biogen- it is a transcription factor which, as a heterodimer with esis, or translation, and do not immediately suggest a unitary mechanism for how Myc works. To make mat- ters worse, there has been controversy over the validity 1 E-MAIL [email protected]; FAX (206) 667-6522. of a number of the candidate target genes. For example, Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ gad928101. in a rat cell line in which c-myc has been deleted, the GENES & DEVELOPMENT 15:2023–2030 © 2001 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/01 $5.00; www.genesdev.org 2023 Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Eisenman introduction and activation of exogenous c-myc results large complex containing histone acetyltransferase in rescue of its slow proliferation phenotype (Mateyak et (HAT) activity. TRRAP was purified as a 400 kD protein al. 1997). However, an analysis of Myc target genes in associated with the controversial Myc Box II region of these cells indicated that only one of nine appeared de- c-Myc, mentioned above (McMahon et al. 1998). TRRAP pendent on Myc for activation (Bush et al. 1998). Given was also identified as a subunit common to several HAT- the relatively weak transcriptional activity of Myc, this containing complexes including hGCN5/PCAF and and other studies raised the possibility that many pre- Tip60/NuA4(Vassilev et al. 1998; Ikura et al. 2000). A sumed targets are either unimportant, incorrect, or indi- yeast TRRAP ortholog, Tra1p, is a component of the rect, and that activation of transcription by Myc may yeast SAGA transcription complex which also possesses likewise be irrelevant (for review, see Cole and McMa- HAT activity as well as other factors that are thought to hon 1999). influence positioning of the basal transcription machin- Although the Myc morass seemed intractable, work ery (Saleh et al. 1998). Putative dominant negative mu- from several different areas has recently converged to tants of TRRAP inhibit Myc transforming activity, indi- confirm and extend the notion that Myc, and other Max cating that interaction with TRRAP is important for at interacting proteins such as the Mad repressor (thought least this aspect of Myc biology. The implication that to be an antagonist of Myc), function through modula- TRRAP binding to Myc results in HAT recruitment has tion of target gene expression. First, both Myc and Mad recently been confirmed by coimmunoprecipitation ex- have been found in complexes which possess histone periments showing that endogenous Myc–Max het- modifying activities (for review, see Knoepfler and Eisen- erodimers are associated with hGCN5 and HAT activity man 1999; Amati et al. 2001). Second, in two papers in (McMahon et al. 2000). this issue (Bouchard et al. 2001; Frank et al. 2001) the Two other functions relating to chromatin-mediated effects of Myc and Mad on the chromatin structure of a transcriptional activity are associated with Myc. The number of target genes are shown to be consistent with TIP48/TIP49 proteins, which possess ATPase/helicase the functions of the transcription complexes which they activities, are detected in association with the Myc N- recruit. In addition, other recent work has begun to re- terminal transactivation region, and a Tip49 mutation in veal both the mechanism and importance of Myc repres- its ATPase region dominantly interferes with Myc onco- sion (Seoane et al. 2001; Staller et al. 2001). Finally, a genicity (Wood et al. 2000). As Tip48 and Tip49 require deeper understanding of the biology of Myc function has Myc Box II for interaction with Myc (Wood et al. 2000), furnished a rationale for the role and number of Myc and have also been found to be subunits of a TRRAP– target genes. Tip60 HAT complex (Ikura et al. 2000), it is plausible that TRAPP mediates binding of the TIP60 complex with Myc, although this remains to be examined in more SINful TRRAPing and TIPing of transcriptional detail. A third chromatin modifying activity reported to activities be associated with Myc is INI1 (Cheng et al. 1999), an Delineating the underlying mechanism through which ortholog of yeast SNF5, which is a subunit of the SWI/ Myc and Mad modulate transcription would bolster the SNF ATP-dependent chromatin remodeling complex argument that their transcriptional activities are an in- (Wang et al. 1996). trinsic part of their function rather than secondary ef- fects or assay artifacts. This was first shown for the Mad Myc and Mad mediate histone acetylation proteins which contain a clearly defined N-terminal re- and deacetylation pression domain that associates directly with the highly conserved corepressor Sin3 (Ayer et al. 1995; Schreiber- The association of Mad proteins with HDACs, and of Agus et al. 1995; Brubaker et al. 2000). That Sin3 in turn Myc proteins with HATs, leads to the prediction that binds the class I histone deacetylases HDAC1 and these histone modifying activities will be manifested at HDAC2 immediately suggests that Mad–Max recruits Mad and Myc binding sites in chromatin.
Load more

Recommended publications
  • TF Activation Profiling Plate Array II Signosis, Inc
    Signosis, Inc. Innovative Plate Assay Solutions TF Activation Profiling Plate Array II Catalog Number: FA-1002 (For Research Use Only) Introduction Materials Provided with the Kit Transcription factors (TFs) are a group of cellular proteins that play essential roles in regulating gene Component Qty Store at expression. They act as sensors to monitor cellular 96-Well Plates (with 2 RT changes and convert signals into gene expression. aluminum adhesive seal) Often, a specific cellular signal pathway can activate Isolation Columns 2 RT multiple TFs. The expression of a specific gene can Elution Buffer 400µL RT also be under the control of multiple TFs. Thus, TF Plate Hybridization Buffer 20mL RT monitoring the activation of multiple TFs 5X Plate Hybridization Wash 60mL RT simultaneously is critical to understanding the Buffer molecular mechanism of cellular regulation underlying 5X Detection Wash Buffer 60mL RT cell signaling and gene expression. Signosis, Inc.’s TF Blocking Buffer 60mL RT Activation Profiling Plate Array II is used for Filter Wash Buffer 5mL 4°C monitoring 96 different TFs simultaneously from one Filter Binding Buffer 1mL 4°C sample. Substrate A 2mL 4°C Substrate B 2mL 4°C Principle of the assay Streptavidin-HRP Conjugate 40µL 4°C Substrate Dilution Buffer 16mL 4°C Signosis, Inc.’s TF Activation Profiling Plate Array II TF Binding Buffer Mix 60µL -20°C is used for monitoring the activation of multiple TFs TF Probe Mix II 20µL -20°C simultaneously. With this technology a series of biotin-labeled probes are made based on the consensus sequences of TF DNA-binding sites.
    [Show full text]
  • Interindividual Regulation of the BCRP/ABCG2 Transporter in Term Human Placentas
    DMD Fast Forward. Published on January 31, 2018 as DOI: 10.1124/dmd.117.079228 This article has not been copyedited and formatted. The final version may differ from this version. DMD #79228 Title Page Interindividual Regulation of the BCRP/ABCG2 Transporter in Term Human Placentas Kristin M Bircsak, Jamie E Moscovitz, Xia Wen, Faith Archer, Poi Yu Sofia Yuen, Moiz Mohammed, Naureen Memon, Barry I Weinberger, Laura M Saba, Anna M Vetrano, Lauren M Aleksunes Downloaded from Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Ernest Mario School of Pharmacy, Piscataway, NJ, USA (K.M.B., J.E.M., X.W., L.M.A.), dmd.aspetjournals.org Department of Pediatrics, Rutgers University Robert Wood Johnson Medical School, New Brunswick, NJ, USA (F.A., P.Y.S.Y, M.M., N.M., A.M.V.), Hofstra Northwell School of Medicine, Cohen Children’s Medical Center of New York, New Hyde Park, NY, USA (B.I.W.), at ASPET Journals on October 2, 2021 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA (L.S.), Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ, USA (L.M.A.), Lipid Center, Rutgers, The State University of New Jersey, Piscataway, NJ, USA (L.M.A.) 1 DMD Fast Forward. Published on January 31, 2018 as DOI: 10.1124/dmd.117.079228 This article has not been copyedited and formatted. The final version may differ from this version. DMD #79228 Running Title Page Running title: Interindividual
    [Show full text]
  • Transcriptional Integration of Mitogenic and Mechanical Signals by Myc and YAP
    Downloaded from genesdev.cshlp.org on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press RESEARCH COMMUNICATION rum-mediated and growth factor-mediated cell cycle Transcriptional integration entry (Kelly et al. 1983; Armelin et al. 1984; Roussel of mitogenic and mechanical et al. 1991; Barone and Courtneidge 1995; de Alboran et al. 2001; Trumpp et al. 2001; Perna et al. 2012). This signals by Myc and YAP function of Myc stems from its ability to control the ex- pression of a large fraction of genes involved in cell activa- Ottavio Croci,1,5 Serena De Fazio,1,5 1,5 1,4,5 tion and proliferation. Francesca Biagioni, Elisa Donato, When ectopically expressed in quiescent cells, Myc is Marieta Caganova,1 Laura Curti,1 Mirko Doni,2 able to drive cell cycle progression in the absence of serum Silvia Sberna,1 Deborah Aldeghi,1 (Eilers et al. 1991; Pelengaris et al. 1999). This effect of Chiara Biancotto,1 Alessandro Verrecchia,2 Myc is context-dependent, however, since not all cells or tissues respond to Myc by entering the cell cycle (Jack- Daniela Olivero,3 Bruno Amati,1,2 1 son et al. 1990; Xiao et al. 2001; Murphy et al. 2008). This and Stefano Campaner suggests that a full proliferative response may require the engagement of other TFs, which may respond to different 1Center for Genomic Science of IIT@SEMM (Istituto Italiano di regulatory signals, such as metabolic or mechanical cues. Tecnologia at European School of Molecular Medicine), Recently, YAP has emerged as a key TF in the control of Fondazione Istituto Italiano di Tecnologia (IIT), 20139 Milan, cell growth and organ size in response to a variety of Italy; 2Department of Experimental Oncology, European signals such as cell adhesion, apico–basolateral polarity, Institute of Oncology (IEO), 20139 Milan, Italy; 3Laboratorio di cytoskeletal tension, and mitogens.
    [Show full text]
  • A Dissertation Entitled the Androgen Receptor
    A Dissertation entitled The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit Submitted to the Graduate Faculty as partial fulfillment of the requirements for the PhD Degree in Biomedical science Dr. Manohar Ratnam, Committee Chair Dr. Lirim Shemshedini, Committee Member Dr. Robert Trumbly, Committee Member Dr. Edwin Sanchez, Committee Member Dr. Beata Lecka -Czernik, Committee Member Dr. Patricia R. Komuniecki, Dean College of Graduate Studies The University of Toledo August 2011 Copyright 2011, Mesfin Gonit This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of The Androgen Receptor as a Transcriptional Co-activator: Implications in the Growth and Progression of Prostate Cancer By Mesfin Gonit As partial fulfillment of the requirements for the PhD Degree in Biomedical science The University of Toledo August 2011 Prostate cancer depends on the androgen receptor (AR) for growth and survival even in the absence of androgen. In the classical models of gene activation by AR, ligand activated AR signals through binding to the androgen response elements (AREs) in the target gene promoter/enhancer. In the present study the role of AREs in the androgen- independent transcriptional signaling was investigated using LP50 cells, derived from parental LNCaP cells through extended passage in vitro. LP50 cells reflected the signature gene overexpression profile of advanced clinical prostate tumors. The growth of LP50 cells was profoundly dependent on nuclear localized AR but was independent of androgen. Nevertheless, in these cells AR was unable to bind to AREs in the absence of androgen.
    [Show full text]
  • Supplemental Table 1. Primers and Probes for RT-Pcrs
    Supplemental Table 1. Primers and probes for RT-PCRs Gene Direction Sequence Quantitative RT-PCR E2F1 Forward Primer 5’-GGA TTT CAC ACC TTT TCC TGG AT-3’ Reverse Primer 5’-CCT GGA AAC TGA CCA TCA GTA CCT-3’ Probe 5’-FAM-CGA GCT GGC CCA CTG CTC TCG-TAMRA-3' E2F2 Forward Primer 5'-TCC CAA TCC CCT CCA GAT C-3' Reverse Primer 5'-CAA GTT GTG CGA TGC CTG C-3' Probe 5' -FAM-TCC TTT TGG CCG GCA GCC G-TAMRA-3' E2F3a Forward Primer 5’-TTT AAA CCA TCT GAG AGG TAC TGA TGA-3’ Reverse Primer 5’-CGG CCC TCC GGC AA-3’ Probe 5’-FAM-CGC TTT CTC CTA GCT CCA GCC TTC G-TAMRA-3’ E2F3b Forward Primer 5’-TTT AAA CCA TCT GAG AGG TAC TGA TGA-3’ Reverse Primer 5’-CCC TTA CAG CAG CAG GCA A-3’ Probe 5’-FAM-CGC TTT CTC CTA GCT CCA GCC TTC G-TAMRA-3’ IRF-1 Forward Primer 5’-TTT GTA TCG GCC TGT GTG AAT G-3’ Reverse Primer 5’-AAG CAT GGC TGG GAC ATC A-3’ Probe 5’-FAM-CAG CTC CGG AAC AAA CAG GCA TCC TT-TAMRA-3' IRF-2 Forward Primer 5'-CGC CCC TCG GCA CTC T-3' Reverse Primer 5'-TCT TCC TAT GCA GAA AGC GAA AC-3' Probe 5'-FAM-TTC ATC GCT GGG CAC ACT ATC AGT-TAMRA-3' TBP Forward Primer 5’-CAC GAA CCA CGG CAC TGA TT-3’ Reverse Primer 5’-TTT TCT TGC TGC CAG TCT GGA C-3’ Probe 5’-FAM-TGT GCA CAG GAG CCA AGA GTG AAG A-BHQ1-3’ Primers and Probes for quantitative RT-PCRs were designed using the computer program “Primer Express” (Applied Biosystems, Foster City, CA, USA).
    [Show full text]
  • Your Genes, Your Choices
    Your Genes, Your Choices: Exploring the Issues Raised by Genetic Research by Catherine Baker Table of Contents Acknowledgments . 6 Introduction . 7 Chapter 1 Martin Needs Medical Treatment (or does he?) . 9 Chapter 2 Priya Should Find Out if She Has Inherited a Fatal Disease (or should she?) . 14 Chapter 3 Howard’s Health Is Up to Him (or is it?) . 26 Chapter 4 Carlos and Mollie Can Have a Perfectly Healthy Baby (or can they?) . 35 Chapter 5 Donita Should Cooperate with the Police (or should she?) . 45 Chapter 6 John and Elsa Will Profit from Biotech Farming (or will they?) . 52 Chapter 7 Dr. Lu’s Patients Have the Right to Be Tall (or do they?) . 62 Chapter 8 Mrs. Fister Can Replace Her Dying Son (or can she?) . 70 Glossary . 81 References . 89 Credits . 81 Science + Literacy for Health Human Genome Project Advisory Board . 93 5 Acknowledgments I am not a science writer by trade. In order to write this book, I first had to study up on genetics and the issues involved. Then I had to try to explain them in a way that other newcomers to the subject could understand, without making terrible errors. It was a difficult task! I am therefore indebted to the members of the AAAS Advisory Panel (listed on page 82). At an all-day meeting in the spring of 1995, they steered my away from my original outline toward the book you find here. Many months later, several panel members provided very useful reviews of the manuscript. For this, I would like to thank Ruth Allen, Jeffrey Botkin, Ron Cole-Turner, Robert Cook-Deegan, and Joan Weiss.
    [Show full text]
  • Structure and Mechanism of the RNA Polymerase II Transcription Machinery
    Downloaded from genesdev.cshlp.org on October 9, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Structure and mechanism of the RNA polymerase II transcription machinery Allison C. Schier and Dylan J. Taatjes Department of Biochemistry, University of Colorado, Boulder, Colorado 80303, USA RNA polymerase II (Pol II) transcribes all protein-coding ingly high resolution, which has rapidly advanced under- genes and many noncoding RNAs in eukaryotic genomes. standing of the molecular basis of Pol II transcription. Although Pol II is a complex, 12-subunit enzyme, it lacks Structural biology continues to transform our under- the ability to initiate transcription and cannot consistent- standing of complex biological processes because it allows ly transcribe through long DNA sequences. To execute visualization of proteins and protein complexes at or near these essential functions, an array of proteins and protein atomic-level resolution. Combined with mutagenesis and complexes interact with Pol II to regulate its activity. In functional assays, structural data can at once establish this review, we detail the structure and mechanism of how enzymes function, justify genetic links to human dis- over a dozen factors that govern Pol II initiation (e.g., ease, and drive drug discovery. In the past few decades, TFIID, TFIIH, and Mediator), pausing, and elongation workhorse techniques such as NMR and X-ray crystallog- (e.g., DSIF, NELF, PAF, and P-TEFb). The structural basis raphy have been complemented by cryoEM, cross-linking for Pol II transcription regulation has advanced rapidly mass spectrometry (CXMS), and other methods. Recent in the past decade, largely due to technological innova- improvements in data collection and imaging technolo- tions in cryoelectron microscopy.
    [Show full text]
  • "The Genecards Suite: from Gene Data Mining to Disease Genome Sequence Analyses". In: Current Protocols in Bioinformat
    The GeneCards Suite: From Gene Data UNIT 1.30 Mining to Disease Genome Sequence Analyses Gil Stelzer,1,5 Naomi Rosen,1,5 Inbar Plaschkes,1,2 Shahar Zimmerman,1 Michal Twik,1 Simon Fishilevich,1 Tsippi Iny Stein,1 Ron Nudel,1 Iris Lieder,2 Yaron Mazor,2 Sergey Kaplan,2 Dvir Dahary,2,4 David Warshawsky,3 Yaron Guan-Golan,3 Asher Kohn,3 Noa Rappaport,1 Marilyn Safran,1 and Doron Lancet1,6 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel 2LifeMap Sciences Ltd., Tel Aviv, Israel 3LifeMap Sciences Inc., Marshfield, Massachusetts 4Toldot Genetics Ltd., Hod Hasharon, Israel 5These authors contributed equally to the paper 6Corresponding author GeneCards, the human gene compendium, enables researchers to effectively navigate and inter-relate the wide universe of human genes, diseases, variants, proteins, cells, and biological pathways. Our recently launched Version 4 has a revamped infrastructure facilitating faster data updates, better-targeted data queries, and friendlier user experience. It also provides a stronger foundation for the GeneCards suite of companion databases and analysis tools. Improved data unification includes gene-disease links via MalaCards and merged biological pathways via PathCards, as well as drug information and proteome expression. VarElect, another suite member, is a phenotype prioritizer for next-generation sequencing, leveraging the GeneCards and MalaCards knowledgebase. It au- tomatically infers direct and indirect scored associations between hundreds or even thousands of variant-containing genes and disease phenotype terms. Var- Elect’s capabilities, either independently or within TGex, our comprehensive variant analysis pipeline, help prepare for the challenge of clinical projects that involve thousands of exome/genome NGS analyses.
    [Show full text]
  • Mouse VDR / NR1I1 Protein (His Tag)
    Mouse VDR / NR1I1 Protein (His Tag) Catalog Number: 51106-M08B General Information SDS-PAGE: Gene Name Synonym: Nr1i1 Protein Construction: A DNA sequence encoding the mouse VDR (P48281) (Met1-Ser422) was fused with a polyhistidine tag at the C-terminus. Source: Mouse Expression Host: Baculovirus-Insect Cells QC Testing Purity: > 80 % as determined by SDS-PAGE Endotoxin: Protein Description < 1.0 EU per μg of the protein as determined by the LAL method VDR (vitamin D(1,25- dihydroxyvitamin D3)receptor), also known as NR1I1, Stability: belongs to the NR1I family, NR1 subfamily. It is composed of three domains: a modulating N-terminal domain, a DNA-binding domain and a C-terminal ℃ Samples are stable for up to twelve months from date of receipt at -70 ligand-binding domain. Vitamin D receptors (VDRs) are members of the NR1I family, which also includes pregnane X (PXR) and constitutive Met Predicted N terminal: androstane (CAR) receptors, that form heterodimers with members of the Molecular Mass: retinoid X receptor family. VDRs repress expression of 1alpha-hydroxylase (the proximal activator of 1,25(OH)2D3) and induce expression of the The recombinant mouse VDR consists of 432 amino acids and has a 1,25(OH)2D3 inactivating enzyme CYP24. Also, it has recently been calculated molecular mass of 49.2 kDa. The recombinant protein migrates identified as an additional bile acid receptor alongside FXR and may as an approximately 55 kDa band in SDS-PAGE under reducing conditions. function to protect gut against the toxic and carcinogenic effects of these endobiotics. VDR is expressed in the intestine, thyroid and kidney and has Formulation: a vital role in calcium homeostasis.
    [Show full text]
  • Review Vitamin D in Neurological Diseases: a Rationale for a Pathogenic Impact
    Review Vitamin D in Neurological Diseases: A Rationale for a Pathogenic Impact Rita Moretti, Maria Elisa Morelli and Paola Caruso * Neurology Clinic, Department of Medical, Surgical and Health Sciences, University of Trieste, Strada di Fiume, 447, 34149, Trieste, Italy; [email protected] (R.M.); [email protected] (M.E.M.) * Correspondence: [email protected] Received: 27 June 2018; Accepted: 26 July 2018; Published: 31 July 2018 Abstract: It is widely known that vitamin D receptors have been found in neurons and glial cells, and their highest expression is in the hippocampus, hypothalamus, thalamus and subcortical grey nuclei, and substantia nigra. Vitamin D helps the regulation of neurotrophin, neural differentiation, and maturation, through the control operation of growing factors synthesis (i.e., neural growth factor [NGF] and glial cell line-derived growth factor (GDNF), the trafficking of the septohippocampal pathway, and the control of the synthesis process of different neuromodulators (such as acetylcholine [Ach], dopamine [DA], and gamma-aminobutyric [GABA]). Based on these assumptions, we have written this review to summarize the potential role of vitamin D in neurological pathologies. This work could be titanic and the results might have been very fuzzy and even incoherent had we not conjectured to taper our first intentions and devoted our interests towards three mainstreams, demyelinating pathologies, vascular syndromes, and neurodegeneration. As a result of the lack of useful therapeutic options, apart from the disease- modifying strategies, the role of different risk factors should be investigated in neurology, as their correction may lead to the improvement of the cerebral conditions. We have explored the relationships between the gene-environmental influence and long-term vitamin D deficiency, as a risk factor for the development of different types of neurological disorders, along with the role and the rationale of therapeutic trials with vitamin D implementation.
    [Show full text]
  • The General Transcription Factors of RNA Polymerase II
    Downloaded from genesdev.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW The general transcription factors of RNA polymerase II George Orphanides, Thierry Lagrange, and Danny Reinberg 1 Howard Hughes Medical Institute, Department of Biochemistry, Division of Nucleic Acid Enzymology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854-5635 USA Messenger RNA (mRNA) synthesis occurs in distinct unique functions and the observation that they can as- mechanistic phases, beginning with the binding of a semble at a promoter in a specific order in vitro sug- DNA-dependent RNA polymerase to the promoter re- gested that a preinitiation complex must be built in a gion of a gene and culminating in the formation of an stepwise fashion, with the binding of each factor promot- RNA transcript. The initiation of mRNA transcription is ing association of the next. The concept of ordered as- a key stage in the regulation of gene expression. In eu- sembly recently has been challenged, however, with the karyotes, genes encoding mRNAs and certain small nu- discovery that a subset of the GTFs exists in a large com- clear RNAs are transcribed by RNA polymerase II (pol II). plex with pol II and other novel transcription factors. However, early attempts to reproduce mRNA transcrip- The existence of this pol II holoenzyme suggests an al- tion in vitro established that purified pol II alone was not ternative to the paradigm of sequential GTF assembly capable of specific initiation (Roeder 1976; Weil et al. (for review, see Koleske and Young 1995).
    [Show full text]
  • Sp1 Transcription Factor: a Long-Standing Target in Cancer Chemotherapy
    Sp1 transcription factor: A long-standing target in cancer chemotherapy Carolina Vizcaíno, Sylvia Mansilla and José Portugal* Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, E-08028 Barcelona, Spain *to whom correspondence should be addressed: Dr. José Portugal, Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Baldiri Reixac, 10; E-08028 Barcelona, Spain. Phone: +34 93 403 4959, FAX: +34 93 403 4979, E-mail: [email protected] 1 ABSTRACT Sp1 (Specificity protein 1) is a well-known member of a family of transcription factors that also includes Sp2, Sp3 and Sp4, which are implicated in an ample variety of essential biological processes and have been proven important in cell growth, differentiation, apoptosis and carcinogenesis. Sp1 activates the transcription of many cellular genes that contain putative CG- rich Sp-binding sites in their promoters. Sp1 and Sp3 proteins bind to similar, if not the same, DNA tracts and compete for binding, thus they can enhance or repress gene expression. Evidences exist that the Sp-family of proteins regulates the expression of genes that play pivotal roles in cell proliferation and metastasis of various tumors. In patients with a variety of cancers, high levels of Sp1 protein are considered a negative prognostic factor. A plethora of compounds can interfere with the trans-activating activities of Sp1 and other Sp proteins on gene expression. Several pathways are involved in the down-regulation of Sp proteins by compounds with different mechanisms of action, which include not only the direct interference with the binding of Sp proteins to their putative DNA binding sites, but also promoting the degradation of Sp protein factors.
    [Show full text]