Cyclin D Activates the Rb Tumor Suppressor by Mono-Phosphorylation
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Clinical and Molecular Relevance of Genetic Variants in the Non-Coding
Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia by Dimitrios Papaioannou, Hatice G. Ozer, Deedra Nicolet, Amog P. Urs, Tobias Herold, Krzysztof Mrózek, Aarif M.N. Batcha, Klaus H. Metzeler, Ayse S. Yilmaz, Stefano Volinia, Marius Bill, Jessica Kohlschmidt, Maciej Pietrzak, Christopher J. Walker, Andrew J. Carroll, Jan Braess, Bayard L. Powell, Ann-Kathrin Eisfeld, Geoffrey L. Uy, Eunice S. Wang, Jonathan E. Kolitz, Richard M. Stone, Wolfgang Hiddemann, John Byrd, Clara D. Bloomfield, and Ramiro Garzon Haematologica 2021 [Epub ahead of print] Citation: Dimitrios Papaioannou, Hatice G. Ozer, Deedra Nicolet, Amog P. Urs, Tobias Herold, Krzysztof Mrózek, Aarif M.N. Batcha, Klaus H. Metzeler, Ayse S. Yilmaz, Stefano Volinia, Marius Bill, Jessica Kohlschmidt, Maciej Pietrzak, Christopher J. Walker, Andrew J. Carroll, Jan Braess, Bayard L. Powell, Ann-Kathrin Eisfeld, Geoffrey L. Uy, Eunice S. Wang, Jonathan E. Kolitz, Richard M. Stone, Wolfgang Hiddemann, John Byrd, Clara D. Bloomfield, and Ramiro Garzon. Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia. Haematologica. 2021; 106:xxx doi:10.3324/haematol.2021.266643 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appear in print on a regular issue of the journal. -
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. -
Role of CREB/CRTC1-Regulated Gene Transcription During Hippocampal-Dependent Memory in Alzheimer’S Disease Mouse Models
ADVERTIMENT. Lʼaccés als continguts dʼaquesta tesi queda condicionat a lʼacceptació de les condicions dʼús establertes per la següent llicència Creative Commons: http://cat.creativecommons.org/?page_id=184 ADVERTENCIA. El acceso a los contenidos de esta tesis queda condicionado a la aceptación de las condiciones de uso establecidas por la siguiente licencia Creative Commons: http://es.creativecommons.org/blog/licencias/ WARNING. The access to the contents of this doctoral thesis it is limited to the acceptance of the use conditions set by the following Creative Commons license: https://creativecommons.org/licenses/?lang=en Institut de Neurociències Universitat Autònoma de Barcelona Departament de Bioquímica i Biologia Molecular Unitat de Bioquímica, Facultat de Medicina Role of CREB/CRTC1-regulated gene transcription during hippocampal-dependent memory in Alzheimer’s disease mouse models Arnaldo J. Parra Damas TESIS DOCTORAL Bellaterra, 2015 Institut de Neurociències Departament de Bioquímica i Biologia Molecular Universitat Autònoma de Barcelona Role of CREB/CRTC1-regulated gene transcription during hippocampal-dependent memory in Alzheimer’s disease mouse models Papel de la transcripción génica regulada por CRTC1/CREB durante memoria dependiente de hipocampo en modelos murinos de la enfermedad de Alzheimer Memoria de tesis doctoral presentada por Arnaldo J. Parra Damas para optar al grado de Doctor en Neurociencias por la Universitat Autonòma de Barcelona. Trabajo realizado en la Unidad de Bioquímica y Biología Molecular de la Facultad de Medicina del Departamento de Bioquímica y Biología Molecular de la Universitat Autònoma de Barcelona, y en el Instituto de Neurociencias de la Universitat Autònoma de Barcelona, bajo la dirección del Doctor Carlos Saura Antolín. -
The Essential Role of the Crtc2-CREB Pathway in Β Cell Function And
The Essential Role of the Crtc2-CREB Pathway in β cell Function and Survival by Chandra Eberhard A thesis submitted to the School of Graduate Studies and Research in partial fulfillment of the requirements for the degree of Masters of Science in Cellular and Molecular Medicine Department of Cellular and Molecular Medicine Faculty of Medicine University of Ottawa September 28, 2012 © Chandra Eberhard, Ottawa, Canada, 2013 Abstract: Immunosuppressants that target the serine/threonine phosphatase calcineurin are commonly administered following organ transplantation. Their chronic use is associated with reduced insulin secretion and new onset diabetes in a subset of patients, suggestive of pancreatic β cell dysfunction. Calcineurin plays a critical role in the activation of CREB, a key transcription factor required for β cell function and survival. CREB activity in the islet is activated by glucose and cAMP, in large part due to activation of Crtc2, a critical coactivator for CREB. Previous studies have demonstrated that Crtc2 activation is dependent on dephosphorylation regulated by calcineurin. In this study, we sought to evaluate the impact of calcineurin-inhibiting immunosuppressants on Crtc2-CREB activation in the primary β cell. In addition, we further characterized the role and regulation of Crtc2 in the β cell. We demonstrate that Crtc2 is required for glucose dependent up-regulation of CREB target genes. The phosphatase calcineurin and kinase regulation by LKB1 contribute to the phosphorylation status of Crtc2 in the β cell. CsA and FK506 block glucose-dependent dephosphorylation and nuclear translocation of Crtc2. Overexpression of a constitutively active mutant of Crtc2 that cannot be phosphorylated at Ser171 and Ser275 enables CREB activity under conditions of calcineurin inhibition. -
Trim24 Targets Endogenous P53 for Degradation
Trim24 targets endogenous p53 for degradation Kendra Alltona,b,1, Abhinav K. Jaina,b,1, Hans-Martin Herza, Wen-Wei Tsaia,b, Sung Yun Jungc, Jun Qinc, Andreas Bergmanna, Randy L. Johnsona,b, and Michelle Craig Bartona,b,2 aDepartment of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences and bCenter for Stem Cell and Developmental Biology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; and cDepartment of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030 Edited by Carol L. Prives, Columbia University, New York, NY, and approved May 15, 2009 (received for review December 23, 2008) Numerous studies focus on the tumor suppressor p53 as a protector regulator of p53 suggests that potential therapeutic targets to of genomic stability, mediator of cell cycle arrest and apoptosis, restore p53 functions remain to be identified. and target of mutation in 50% of all human cancers. The vast majority of information on p53, its protein-interaction partners and Results and Discussion regulation, comes from studies of tumor-derived, cultured cells Creation of a Mouse and Stem Cell Model for p53 Analysis. To where p53 and its regulatory controls may be mutated or dysfunc- facilitate analysis of endogenous p53 in normal cells, we per- tional. To address regulation of endogenous p53 in normal cells, formed gene targeting to create mouse embryonic stem (ES) we created a mouse and stem cell model by knock-in (KI) of a cells and mice (12), which express endogenously regulated p53 tandem-affinity-purification (TAP) epitope at the endogenous protein fused with a C-terminal TAP tag (p53-TAPKI, Fig. -
Mitogen Requirement for Cell Cycle Progression in the Absence of Pocket Protein Activity
ARTICLE Mitogen requirement for cell cycle progression in the absence of pocket protein activity Floris Foijer,1 Rob M.F. Wolthuis,1 Valerie Doodeman,1 Rene´ H. Medema,2 and Hein te Riele1,* 1 Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands 2 Present address: Experimental Oncology, University Medical Center, Stratenum 2.103, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands *Correspondence: [email protected] Summary Primary mouse embryonic fibroblasts lacking expression of all three retinoblastoma protein family members (TKO MEFs) have lost the G1 restriction point. However, in the absence of mitogens these cells become highly sensitive to apoptosis. CIP1 KIP1 Here, we show that TKO MEFs that survive serum depletion pass G1 but completely arrest in G2. p21 and p27 inhibit Cyclin A-Cdk2 activity and sequester Cyclin B1-Cdk1 in inactive complexes in the nucleus. This response is alleviated by mi- togen restimulation or inactivation of p53. Thus, our results disclose a cell cycle arrest mechanism in G2 that restricts the proliferative capacity of mitogen-deprived cells that have lost the G1 restriction point. The involvement of p53 provides a ra- tionale for the synergism between loss of Rb and p53 in tumorigenesis. Introduction Despite the critical role of pRb in controlling the G1 restriction point, pRb knockout primary mouse embryonic fibroblasts Proliferation of cells in culture is dependent on the presence of (MEFs) do not proliferate in the absence of mitogens but still ar- mitogenic stimuli. In the absence of mitogens, cells fail to prog- rest (Herrera et al., 1996; Almasan et al., 1995). -
Runx3 Plays a Critical Role in Restriction-Point and Defense Against Cellular Transformation
OPEN Oncogene (2017) 36, 6884–6894 www.nature.com/onc ORIGINAL ARTICLE Runx3 plays a critical role in restriction-point and defense against cellular transformation X-Z Chi1, J-W Lee1, Y-S Lee1, IY Park2,YIto3 and S-C Bae1 The restriction (R)-point decision is fundamental to normal differentiation and the G1–S transition, and the decision-making machinery is perturbed in nearly all cancer cells. The mechanisms underlying the cellular context–dependent R-point decision remain poorly understood. We found that the R-point was dysregulated in Runx3−/−mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenicity of Runx3−/−MEFs and K-Ras–activated Runx3−/−MEFs (Runx3−/−;K-RasG12D/+). During the R-point, Runx3 transiently formed a complex with pRb and Brd2 and induced Cdkn1a (p21Waf1/Cip1/Sdi1; p21), a key regulator of the R-point transition. Cyclin D–CDK4/6 promoted dissociation of the pRb–Runx3–Brd2 complex, thus turning off p21 expression. However, cells harboring oncogenic K-Ras maintained the pRb– Runx3–Brd2 complex and p21 expression even after introduction of Cyclin D1. Thus, Runx3 plays a critical role in R-point regulation and defense against cellular transformation. Oncogene (2017) 36, 6884–6894; doi:10.1038/onc.2017.290; published online 28 August 2017 INTRODUCTION general, the p53 pathway is inactivated during MEF immortaliza- The restriction (R)-point is a critical event in which a mammalian tion, but the immortalized MEFs are not tumorigenic, which cell makes the decision in response to mitogen stimulation. -
DNA Damage Triggers a Prolonged P53- Dependent G^ Arrest Ana Long-Term Induction of Cipl in Normal Human Fibroblasts
Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press DNA damage triggers a prolonged p53- dependent G^ arrest ana long-term induction of Cipl in normal human fibroblasts Aldo Di Leonardo/'^'^ Steven P. Linke/'^'^ Kris Clarkin/ and Geoffrey M. Wahl** ^Gene Expression Lab, The Salk Institute, La Jolla, California 92037 USA; ^Department of Cell and Developmental Biology, University of Palermo, Italy; ^Department of Biology, University of California, San Diego, La Jolla, California 92037 USA The tumor suppressor p53 is a cell cycle checkpoint protein that contributes to the preservation of genetic stability by mediating either a G^ arrest or apoptosis in response to DNA damage. Recent reports suggest that p53 causes growth arrest through transcriptional activation of the cyclin-dependent kinase (Cdk)-inhibitor Cipl. Here, we characterize the p53-dependent Gj arrest in several normal human diploid fibroblast (NDF) strains and p53-deficient cell lines treated with 0.1-6 Gy gamma radiation. DNA damage and cell cycle progression analyses showed that NDF entered a prolonged arrest state resembling senescence, even at low doses of radiation. This contrasts with the view that p53 ensures genetic stability by inducing a transient arrest to enable repair of DNA damage, as reported for some myeloid leukemia lines. Gamma radiation administered in early to mid-, but not late, G^ induced the arrest, suggesting that the p53 checkpoint is only active in Gj until cells commit to enter S phase at the Gi restriction point. A log-linear plot of the fraction of irradiated GQ cells able to enter S phase as a function of dose is consistent with single-hit kinetics. -
Histone Acetyltransferase Activity of CREB-Binding Protein Is Essential
bioRxiv preprint doi: https://doi.org/10.1101/2021.05.26.445902; this version posted July 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Histone acetyltransferase activity of CREB-binding protein is 2 essential for synaptic plasticity in Lymnaea 3 4 Dai Hatakeyama1,2,*, Hiroshi Sunada3, Yuki Totani4, Takayuki Watanabe5,6, Ildikó Felletár1, 5 Adam Fitchett1, Murat Eravci1, Aikaterini Anagnostopoulou1, Ryosuke Miki2, Takashi 6 Kuzuhara2, Ildikó Kemenes1, Etsuro Ito3,4, György Kemenes1,* 7 8 1Sussex Neuroscience, School of Life Sciences, University of Sussex, Brighton BN1 9QG, 9 UK. 2Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, 10 Japan. 3Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Sanuki 11 769-2193, Japan. 4Department of Biology, Waseda University, Tokyo 162-8480, Japan. 12 5Graduate School of Life Science, Hokkaido University, Sapporo 060-0810, Japan. 13 6Laboratory of Neuroethology, Sokendai-Hayama, Hayama 240-0193, Japan. 14 15 Keywords: Long-term memory; Lymnaea; CREB-binding protein (CBP); Histone Acetyl 16 Transferase (HAT); Cerebral Giant Cell (CGC); synaptic plasticity 17 18 *Correspondence should be addressed to Dr. Dai Hatakeyama, Tokushima Bunri University, 19 180 Nishihama-Houji, Yamashiro-cho, Tokushima City, Tokushima 770-8514, Japan, 20 [email protected]; and Prof. György Kemenes, University of Sussex, Brighton, 21 BN1 9QG, United Kingdom, [email protected]. 22 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.05.26.445902; this version posted July 22, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
Loss of P21 Disrupts P14arf-Induced G1 Cell Cycle Arrest but Augments P14arf-Induced Apoptosis in Human Carcinoma Cells
Oncogene (2005) 24, 4114–4128 & 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00 www.nature.com/onc Loss of p21 disrupts p14ARF-induced G1 cell cycle arrest but augments p14ARF-induced apoptosis in human carcinoma cells Philipp G Hemmati1,3, Guillaume Normand1,3, Berlinda Verdoodt1, Clarissa von Haefen1, Anne Hasenja¨ ger1, DilekGu¨ ner1, Jana Wendt1, Bernd Do¨ rken1,2 and Peter T Daniel*,1,2 1Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charite´, Campus Berlin-Buch, Berlin-Buch, Germany; 2Max-Delbru¨ck-Center for Molecular Medicine, Berlin-Buch, Germany The human INK4a locus encodes two structurally p16INK4a and p14ARF (termed p19ARF in the mouse), latter unrelated tumor suppressor proteins, p16INK4a and p14ARF of which is transcribed in an Alternative Reading Frame (p19ARF in the mouse), which are frequently inactivated in from a separate exon 1b (Duro et al., 1995; Mao et al., human cancer. Both the proapoptotic and cell cycle- 1995; Quelle et al., 1995; Stone et al., 1995). P14ARF is regulatory functions of p14ARF were initially proposed to usually expressed at low levels, but rapid upregulation be strictly dependent on a functional p53/mdm-2 tumor of p14ARF is triggered by various stimuli, that is, suppressor pathway. However, a number of recent reports the expression of cellular or viral oncogenes including have implicated p53-independent mechanisms in the E2F-1, E1A, c-myc, ras, and v-abl (de Stanchina et al., regulation of cell cycle arrest and apoptosis induction by 1998; Palmero et al., 1998; Radfar et al., 1998; Zindy p14ARF. Here, we show that the G1 cell cycle arrest et al., 1998). -
Plasma Autoantibodies Associated with Basal-Like Breast Cancers
Published OnlineFirst June 12, 2015; DOI: 10.1158/1055-9965.EPI-15-0047 Research Article Cancer Epidemiology, Biomarkers Plasma Autoantibodies Associated with Basal-like & Prevention Breast Cancers Jie Wang1, Jonine D. Figueroa2, Garrick Wallstrom1, Kristi Barker1, Jin G. Park1, Gokhan Demirkan1, Jolanta Lissowska3, Karen S. Anderson1, Ji Qiu1, and Joshua LaBaer1 Abstract Background: Basal-like breast cancer (BLBC) is a rare aggressive PSRC1, MN1, TRIM21) that distinguished BLBC from controls subtype that is less likely to be detected through mammographic with 33% sensitivity and 98% specificity. We also discovered a screening. Identification of circulating markers associated with strong association of TP53 AAb with its protein expression (P ¼ BLBC could have promise in detecting and managing this deadly 0.009) in BLBC patients. In addition, MN1 and TP53 AAbs were disease. associated with worse survival [MN1 AAb marker HR ¼ 2.25, 95% Methods: Using samples from the Polish Breast Cancer study, a confidence interval (CI), 1.03–4.91; P ¼ 0.04; TP53, HR ¼ 2.02, high-quality population-based case–control study of breast can- 95% CI, 1.06–3.85; P ¼ 0.03]. We found limited evidence that cer, we screened 10,000 antigens on protein arrays using 45 BLBC AAb levels differed by demographic characteristics. patients and 45 controls, and identified 748 promising plasma Conclusions: These AAbs warrant further investigation in autoantibodies (AAbs) associated with BLBC. ELISA assays of clinical studies to determine their value for further understanding promising markers were performed on a total of 145 BLBC cases the biology of BLBC and possible detection. and 145 age-matched controls. -
Trim24-Regulated Estrogen Response Is Dependent on Specific Histone Modifications in Breast Cancer Cells
The Texas Medical Center Library DigitalCommons@TMC The University of Texas MD Anderson Cancer Center UTHealth Graduate School of The University of Texas MD Anderson Cancer Biomedical Sciences Dissertations and Theses Center UTHealth Graduate School of (Open Access) Biomedical Sciences 12-2012 TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE MODIFICATIONS IN BREAST CANCER CELLS Teresa T. Yiu Follow this and additional works at: https://digitalcommons.library.tmc.edu/utgsbs_dissertations Part of the Biochemistry Commons, Cancer Biology Commons, Medicine and Health Sciences Commons, and the Molecular Biology Commons Recommended Citation Yiu, Teresa T., "TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE MODIFICATIONS IN BREAST CANCER CELLS" (2012). The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access). 313. https://digitalcommons.library.tmc.edu/utgsbs_dissertations/313 This Dissertation (PhD) is brought to you for free and open access by the The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences at DigitalCommons@TMC. It has been accepted for inclusion in The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences Dissertations and Theses (Open Access) by an authorized administrator of DigitalCommons@TMC. For more information, please contact [email protected]. TRIM24-REGULATED ESTROGEN RESPONSE IS DEPENDENT ON SPECIFIC HISTONE