Myt1 Kinase Promotes Mitotic Cell Cycle Exit in Drosophila Intestinal Progenitor Cells
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Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons After DNA Damage
The Journal of Neuroscience, July 15, 2001, 21(14):5017–5026 Cyclin-Dependent Kinases and P53 Pathways Are Activated Independently and Mediate Bax Activation in Neurons after DNA Damage Erick J. Morris,1 Elizabeth Keramaris,2 Hardy J. Rideout,3 Ruth S. Slack,2 Nicholas J. Dyson,1 Leonidas Stefanis,3 and David S. Park2 1Massachusetts General Hospital Cancer Center, Laboratory of Molecular Oncology, Charlestown, Massachusetts 02129, 2Neuroscience Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, and 3Columbia University, New York, New York 10032 DNA damage has been implicated as one important initiator of ization, and DNA binding that result from DNA damage are not cell death in neuropathological conditions such as stroke. Ac- affected by the inhibition of CDK activity. Conversely, no de- cordingly, it is important to understand the signaling processes crease in retinoblastoma protein (pRb) phosphorylation was that control neuronal death induced by this stimulus. Previous observed in p53-deficient neurons that were treated with camp- evidence has shown that the death of embryonic cortical neu- tothecin. However, either p53 deficiency or the inhibition of rons treated with the DNA-damaging agent camptothecin is CDK activity alone inhibited Bax translocation, cytochrome c dependent on the tumor suppressor p53 and cyclin-dependent release, and caspase-3-like activation. Taken together, our re- kinase (CDK) activity and that the inhibition of either pathway sults indicate that p53 and CDK are activated independently alone leads to enhanced and prolonged survival. We presently and then act in concert to control Bax-mediated apoptosis. show that p53 and CDKs are activated independently on par- allel pathways. -
The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression
International Journal of Molecular Sciences Review The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression Tingting Zou and Zhenghong Lin * School of Life Sciences, Chongqing University, Chongqing 401331, China; [email protected] * Correspondence: [email protected] Abstract: The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), which activities are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins, CDK inhibitors (CKIs), other kinases and phosphatases. Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell cycle progression via recognition, interaction, and ubiquitination or deubiquitination of key proteins. The illegitimate degradation of tumor suppressor or abnormally high accumulation of oncoproteins often results in deregulation of cell proliferation, genomic instability, and cancer occurrence. In this review, we demonstrate the diversity and complexity of the regulation of UPS machinery of the cell cycle. A profound understanding of the ubiquitination machinery will provide new insights into the regulation of the cell cycle transition, cancer treatment, and the development of anti-cancer drugs. Keywords: cell cycle regulation; CDKs; cyclins; CKIs; UPS; E3 ubiquitin ligases; Deubiquitinases (DUBs) Citation: Zou, T.; Lin, Z. The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression. 1. Introduction Int. J. Mol. Sci. 2021, 22, 5754. https://doi.org/10.3390/ijms22115754 The cell cycle is a ubiquitous, complex, and highly regulated process that is involved in the sequential events during which a cell duplicates its genetic materials, grows, and di- Academic Editors: Kwang-Hyun Bae vides into two daughter cells. -
Transcription of Platelet-Derived Growth Factor Receptor a in Leydig Cells Involves Specificity Protein 1 and 3
125 Transcription of platelet-derived growth factor receptor a in Leydig cells involves specificity protein 1 and 3 Francis Bergeron1, Edward T Bagu1 and Jacques J Tremblay1,2 1Reproduction, Perinatal and Child Health, CHUQ Research Centre, CHUL Room T1-49, 2705 Laurier Boulevard, Que´bec, Que´bec, Canada G1V 4G2 2Department of Obstetrics and Gynecology, Faculty of Medicine, Centre for Research in Biology of Reproduction, Universite´ Laval, Que´bec, Que´bec, Canada G1V 0A6 (Correspondence should be addressed to J J Tremblay; Email: [email protected]) Abstract Platelet-derived growth factor (PDGF) A is secreted by Sertoli cells and acts on Leydig precursor cells, which express the receptor PDGFRA, triggering their differentiation into steroidogenically active Leydig cells. There is, however, no information regarding the molecular mechanisms that govern Pdgfra expression in Leydig cells. In this study, we isolated and characterized a 2.2 kb fragment of the rat Pdgfra 50-flanking sequence in the TM3 Leydig cell line, which endogenously expresses Pdgfra. A series of 50 progressive deletions of the Pdgfra promoter was generated and transfected in TM3 cells. Using this approach, two regions (K183/K154 and K154/K105), each conferring 46% of Pdgfra promoter activity, were identified. To better define the regulatory elements, trinucleotide mutations spanning the K154/K105 region were introduced by site-directed mutagenesis in the context of the K2.2kb Pdgfra promoter. Mutations that altered the TCCGAGGGAAAC sequence at K138 bp significantly decreased Pdgfra promoter activity in TM3 cells. Several proteins from TM3 nuclear extracts were found to bind to this G(C/A) motif in electromobility shift assay. -
A Haploid Genetic Screen Identifies the G1/S Regulatory Machinery As a Determinant of Wee1 Inhibitor Sensitivity
A haploid genetic screen identifies the G1/S regulatory machinery as a determinant of Wee1 inhibitor sensitivity Anne Margriet Heijinka, Vincent A. Blomenb, Xavier Bisteauc, Fabian Degenera, Felipe Yu Matsushitaa, Philipp Kaldisc,d, Floris Foijere, and Marcel A. T. M. van Vugta,1 aDepartment of Medical Oncology, University Medical Center Groningen, University of Groningen, 9723 GZ Groningen, The Netherlands; bDivision of Biochemistry, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; cInstitute of Molecular and Cell Biology, Agency for Science, Technology and Research, Proteos#3-09, Singapore 138673, Republic of Singapore; dDepartment of Biochemistry, National University of Singapore, Singapore 117597, Republic of Singapore; and eEuropean Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, The Netherlands Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved October 21, 2015 (received for review March 17, 2015) The Wee1 cell cycle checkpoint kinase prevents premature mitotic Wee1 kinase at tyrosine (Tyr)-15 to prevent unscheduled Cdk1 entry by inhibiting cyclin-dependent kinases. Chemical inhibitors activity (5, 6). Conversely, timely activation of Cdk1 depends on of Wee1 are currently being tested clinically as targeted anticancer Tyr-15 dephosphorylation by one of the Cdc25 phosphatases drugs. Wee1 inhibition is thought to be preferentially cytotoxic in (7–10). When DNA is damaged, the downstream DNA damage p53-defective cancer cells. However, TP53 mutant cancers do not response (DDR) kinases Chk1 and Chk2 inhibit Cdc25 phos- respond consistently to Wee1 inhibitor treatment, indicating the phatases through direct phosphorylation, which blocks Cdk1 existence of genetic determinants of Wee1 inhibitor sensitivity other activation (11–13). -
1,25 Dihydroxyvitamin D-Mediated Orchestration of Anticancer
Kovalenko et al. BMC Genomics 2010, 11:26 http://www.biomedcentral.com/1471-2164/11/26 RESEARCH ARTICLE Open Access 1,25 dihydroxyvitamin D-mediated orchestration of anticancer, transcript-level effects in the immortalized, non-transformed prostate epithelial cell line, RWPE1 Pavlo L Kovalenko1, Zhentao Zhang1, Min Cui1, Steve K Clinton2, James C Fleet1* Abstract Background: Prostate cancer is the second leading cause of cancer mortality among US men. Epidemiological evidence suggests that high vitamin D status protects men from prostate cancer and the active form of vitamin D, 1a,25 dihydroxyvitamin D3 (1,25(OH)2D) has anti-cancer effects in cultured prostate cells. Still, the molecular mechanisms and the gene targets for vitamin D-mediated prostate cancer prevention are unknown. Results: We examined the effect of 1,25(OH)2D (+/- 100 nM, 6, 24, 48 h) on the transcript profile of proliferating RWPE1 cells, an immortalized, non-tumorigenic prostate epithelial cell line that is growth arrested by 1,25(OH)2D (Affymetrix U133 Plus 2.0, n = 4/treatment per time and dose). Our analysis revealed many transcript level changes at a 5% false detection rate: 6 h, 1571 (61% up), 24 h, 1816 (60% up), 48 h, 3566 (38% up). 288 transcripts were regulated similarly at all time points (182 up, 80 down) and many of the promoters for these transcripts contained putative vitamin D response elements. Functional analysis by pathway or Gene Set Analysis revealed early suppression of WNT, Notch, NF-kB, and IGF1 signaling. Transcripts related to inflammation were suppressed at 6 h (e.g. -
Association of Gene Ontology Categories with Decay Rate for Hepg2 Experiments These Tables Show Details for All Gene Ontology Categories
Supplementary Table 1: Association of Gene Ontology Categories with Decay Rate for HepG2 Experiments These tables show details for all Gene Ontology categories. Inferences for manual classification scheme shown at the bottom. Those categories used in Figure 1A are highlighted in bold. Standard Deviations are shown in parentheses. P-values less than 1E-20 are indicated with a "0". Rate r (hour^-1) Half-life < 2hr. Decay % GO Number Category Name Probe Sets Group Non-Group Distribution p-value In-Group Non-Group Representation p-value GO:0006350 transcription 1523 0.221 (0.009) 0.127 (0.002) FASTER 0 13.1 (0.4) 4.5 (0.1) OVER 0 GO:0006351 transcription, DNA-dependent 1498 0.220 (0.009) 0.127 (0.002) FASTER 0 13.0 (0.4) 4.5 (0.1) OVER 0 GO:0006355 regulation of transcription, DNA-dependent 1163 0.230 (0.011) 0.128 (0.002) FASTER 5.00E-21 14.2 (0.5) 4.6 (0.1) OVER 0 GO:0006366 transcription from Pol II promoter 845 0.225 (0.012) 0.130 (0.002) FASTER 1.88E-14 13.0 (0.5) 4.8 (0.1) OVER 0 GO:0006139 nucleobase, nucleoside, nucleotide and nucleic acid metabolism3004 0.173 (0.006) 0.127 (0.002) FASTER 1.28E-12 8.4 (0.2) 4.5 (0.1) OVER 0 GO:0006357 regulation of transcription from Pol II promoter 487 0.231 (0.016) 0.132 (0.002) FASTER 6.05E-10 13.5 (0.6) 4.9 (0.1) OVER 0 GO:0008283 cell proliferation 625 0.189 (0.014) 0.132 (0.002) FASTER 1.95E-05 10.1 (0.6) 5.0 (0.1) OVER 1.50E-20 GO:0006513 monoubiquitination 36 0.305 (0.049) 0.134 (0.002) FASTER 2.69E-04 25.4 (4.4) 5.1 (0.1) OVER 2.04E-06 GO:0007050 cell cycle arrest 57 0.311 (0.054) 0.133 (0.002) -
Functional Characterisation of MYT1L, a Brain-Specific Transcriptional Regulator
This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Functional characterisation of MYT1L, a brain-specific transcriptional regulator Kepa, Agnieszka Maria Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 04. Oct. 2021 Functional characterisation of MYT1L, a brain-specific transcriptional regulator Agnieszka Kępa 2014 A thesis submitted to King’s College London for the degree of Doctor of Philosophy MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry ABSTRACT Abnormalities in brain development and maladaptive plasticity are thought to underlay a range of neurodevelopmental and neurological disabilities and disorders, such as autism spectrum disorders, schizophrenia and learning disability. -
(12) Patent Application Publication (10) Pub. No.: US 2006/0068395 A1 Wood Et Al
US 2006.0068395A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0068395 A1 Wood et al. (43) Pub. Date: Mar. 30, 2006 (54) SYNTHETIC NUCLEIC ACID MOLECULE (21) Appl. No.: 10/943,508 COMPOSITIONS AND METHODS OF PREPARATION (22) Filed: Sep. 17, 2004 (76) Inventors: Keith V. Wood, Mt. Horeb, WI (US); Publication Classification Monika G. Wood, Mt. Horeb, WI (US); Brian Almond, Fitchburg, WI (51) Int. Cl. (US); Aileen Paguio, Madison, WI CI2O I/68 (2006.01) (US); Frank Fan, Madison, WI (US) C7H 2L/04 (2006.01) (52) U.S. Cl. ........................... 435/6: 435/320.1; 536/23.1 Correspondence Address: SCHWEGMAN, LUNDBERG, WOESSNER & (57) ABSTRACT KLUTH 1600 TCF TOWER A method to prepare synthetic nucleic acid molecules having 121 SOUTHEIGHT STREET reduced inappropriate or unintended transcriptional charac MINNEAPOLIS, MN 55402 (US) teristics when expressed in a particular host cell. Patent Application Publication Mar. 30, 2006 Sheet 1 of 2 US 2006/0068395 A1 Figure 1 Amino Acid Codon Phe UUU, UUC Ser UCU, UCC, UCA, UCG, AGU, AGC Tyr UAU, UAC Cys UGU, UGC Leu UUA, UUG, CUU, CUC, CUA, CUG Trp UGG Pro CCU, CCC, CCA, CCG His CAU, CAC Arg CGU, CGC, CGA, CGG, AGA, AGG Gln CAA, CAG Ile AUU, AUC, AUA Thr ACU, ACC, ACA, ACG ASn AAU, AAC LyS AAA, AAG Met AUG Val GUU, GUC, GUA, GUG Ala GCU, GCC, GCA, GCG Asp GAU, GAC Gly GGU, GGC, GGA, GGG Glu GAA, GAG Patent Application Publication Mar. 30, 2006 Sheet 2 of 2 US 2006/0068395 A1 Spd Sequence pGL4B-4NN3. -
BMC Developmental Biology Biomed Central
BMC Developmental Biology BioMed Central Research article Open Access Identification of known and novel pancreas genes expressed downstream of Nkx2.2 during development Keith R Anderson1, Peter White3,4, Klaus H Kaestner3 and Lori Sussel*1,2 Address: 1Department of Biochemistry and Program in Molecular Biology, University of Colorado Health Science Center, Denver, CO, 80045, USA, 2Department of Genetics and Development, Columbia University, New York, NY 10032, USA, 3Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania, 752B CRB, 415 Curie Blvd, Philadelphia, Pennsylvania 19104, USA and 4The Research Institute at Nationwide Children's Hospital, 700 Childrens Drive, Columbus, OH 43205, USA Email: Keith R Anderson - [email protected]; Peter White - [email protected]; Klaus H Kaestner - [email protected]; Lori Sussel* - [email protected] * Corresponding author Published: 10 December 2009 Received: 27 May 2009 Accepted: 10 December 2009 BMC Developmental Biology 2009, 9:65 doi:10.1186/1471-213X-9-65 This article is available from: http://www.biomedcentral.com/1471-213X/9/65 © 2009 Anderson et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: The homeodomain containing transcription factor Nkx2.2 is essential for the differentiation of pancreatic endocrine cells. Deletion of Nkx2.2 in mice leads to misspecification of islet cell types; insulin-expressing β cells and glucagon-expressing α cells are replaced by ghrelin- expressing cells. -
Upregulation of Myt1 Promotes Acquired Resistance of Cancer Cells to Wee1 Inhibition Cody W
Published OnlineFirst October 8, 2019; DOI: 10.1158/0008-5472.CAN-19-1961 Cancer Molecular Cell Biology Research Upregulation of Myt1 Promotes Acquired Resistance of Cancer Cells to Wee1 Inhibition Cody W. Lewis1,2,3, Amirali B. Bukhari1,2,3, Edric J. Xiao1,3, Won-Shik Choi1,2,3, Joanne D. Smith1,2,3, Ellen Homola4, John R. Mackey1,5, Shelagh D. Campbell4, Armin M. Gamper1,2,3, and Gordon K. Chan1,2,3 Abstract Adavosertib (also known as AZD1775 or MK1775) is a tion of Cdk1 induced aberrant mitosis and cell death by small-molecule inhibitor of the protein kinase Wee1, with mitotic catastrophe. Cancer cells with intrinsic adavosertib single-agent activity in multiple solid tumors, including sar- resistance had higher levels of Myt1 compared with sensitive coma, glioblastoma, and head and neck cancer. Adavosertib cells. Furthermore, cancer cells that acquired resistance fol- also shows promising results in combination with genotoxic lowing short-term adavosertib treatment had higher levels of agents such as ionizing radiation or chemotherapy. Previous Myt1 compared with mock-treated cells. Downregulating studies have investigated molecular mechanisms of primary Myt1 enhanced ectopic Cdk1 activity and restored sensitivity resistance to Wee1 inhibition. Here, we investigated mechan- to adavosertib. These data demonstrate that upregulating Myt1 isms of acquired resistance to Wee1 inhibition, focusing on the is a mechanism by which cancer cells acquire resistance to role of the Wee1-related kinase Myt1. Myt1 and Wee1 kinases adavosertib. were both capable of phosphorylating and inhibiting Cdk1/ cyclin B, the key enzymatic complex required for mitosis, Significance: Myt1 is a candidate predictive biomarker of demonstrating their functional redundancy. -
MYT1 Protein MYT1 Protein
Catalogue # Aliquot Size M67-34G-20 20 µg M67-34G-50 50 µg MYT1 Protein Full length recombinant protein expressed in Sf9 cells Catalog # M67-34G Lot # N353 -3 Product Description Purity Recombinant full-length human MYT1 was expressed by baculovirus in Sf9 insect cells using an N-terminal GST tag. The gene accession number is NM_004203 . The purity was determined to be Gene Aliases >80% by densitometry. Approx. MW 93 kDa . PKMYT1, FLJ20093, DKFZp547K1610 Formulation Recombinant protein stored in 50mM Tris-HCl, pH 7.5, 50mM NaCl, 10mM glutathione, 0.1mM EDTA, 0.25mM DTT, 0.1mM PMSF, 25% glycerol. Storage and Stability Store product at –70 oC. For optimal storage, aliquot target into smaller quantities after centrifugation and store at recommended temperature. For most favorable performance, avoid repeated handling and multiple freeze/thaw cycles. Scientific Background MYT1 is a member of a family of neural specific, zinc finger-containing DNA-binding proteins which binds to the promoter regions of proteolipid proteins of the central nervous system and plays a role in the developing nervous system. MYT1 of the oligodendrocyte lineage, along with a closely related CCHC zinc finger, is MYT1 Protein expressed in developing neurons in the mammalian Full length recombinant protein expressed in Sf9 cells central nervous system(1). The recombinant MYT1 fragments containing either the upstream 2 zinc fingers or Catalog Number M67-34G the downstream 4 zinc fingers bound the same cis Specific Lot Number N353-3 regulatory element in the PLP1 promoter in vitro and DNA Purity >80% binding required Zn(2+), but not other divalent cations Concentration 0.1 µ g/ µl Stability 1yr At –70 oC from date of shipment (2). -
Myt1l Safeguards Neuronal Identity by Actively Repressing Many Non-Neuronal Fates Moritz Mall1, Michael S
LETTER doi:10.1038/nature21722 Myt1l safeguards neuronal identity by actively repressing many non-neuronal fates Moritz Mall1, Michael S. Kareta1†, Soham Chanda1,2, Henrik Ahlenius3, Nicholas Perotti1, Bo Zhou1,2, Sarah D. Grieder1, Xuecai Ge4†, Sienna Drake3, Cheen Euong Ang1, Brandon M. Walker1, Thomas Vierbuchen1†, Daniel R. Fuentes1, Philip Brennecke5†, Kazuhiro R. Nitta6†, Arttu Jolma6, Lars M. Steinmetz5,7, Jussi Taipale6,8, Thomas C. Südhof2 & Marius Wernig1 Normal differentiation and induced reprogramming require human Myt1l (Extended Data Fig. 1). Chromatin immunoprecipita- the activation of target cell programs and silencing of donor cell tion followed by DNA sequencing (ChIP–seq) of endogenous Myt1l programs1,2. In reprogramming, the same factors are often used to in fetal neurons (embryonic day (E) 13.5) and ectopic Myt1l in mouse reprogram many different donor cell types3. As most developmental embryonic fibroblasts (MEFs) two days after induction identified 3,325 repressors, such as RE1-silencing transcription factor (REST) and high-confidence Myt1l peaks that overlapped remarkably well between Groucho (also known as TLE), are considered lineage-specific neurons and MEFs (Fig. 1a, Extended Data Fig. 2, Supplementary repressors4,5, it remains unclear how identical combinations of Table 1). Thus, similar to the pioneer factor Ascl1, Myt1l can access transcription factors can silence so many different donor programs. the majority of its cognate DNA binding sites even in a distantly related Distinct lineage repressors would have to be induced in different cell type. However, unlike Ascl1 targets8, the chromatin at Myt1l donor cell types. Here, by studying the reprogramming of mouse fibroblasts to neurons, we found that the pan neuron-specific a Myt1l Myt1l b Myt1l Ascl1 Random Myt1l 6 Ascl1 + Brn2 endogenous transcription factor Myt1-like (Myt1l) exerts its pro-neuronal Closed 0.030 function by direct repression of many different somatic lineage k programs except the neuronal program.