Phosphatases Reverse P53-Mediated Cell Cycle Checkpoints
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Deciphering the Functions of Ets2, Pten and P53 in Stromal Fibroblasts in Multiple
Deciphering the Functions of Ets2, Pten and p53 in Stromal Fibroblasts in Multiple Breast Cancer Models DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Julie Wallace Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2013 Dissertation Committee: Michael C. Ostrowski, PhD, Advisor Gustavo Leone, PhD Denis Guttridge, PhD Dawn Chandler, PhD Copyright by Julie Wallace 2013 Abstract Breast cancer is the second most common cancer in American women, and is also the second leading cause of cancer death in women. It is estimated that nearly a quarter of a million new cases of invasive breast cancer will be diagnosed in women in the United States this year, and approximately 40,000 of these women will die from breast cancer. Although death rates have been on the decline for the past decade, there is still much we need to learn about this disease to improve prevention, detection and treatment strategies. The majority of early studies have focused on the malignant tumor cells themselves, and much has been learned concerning mutations, amplifications and other genetic and epigenetic alterations of these cells. However more recent work has acknowledged the strong influence of tumor stroma on the initiation, progression and recurrence of cancer. Under normal conditions this stroma has been shown to have protective effects against tumorigenesis, however the transformation of tumor cells manipulates this surrounding environment to actually promote malignancy. Fibroblasts in particular make up a significant portion of this stroma, and have been shown to impact various aspects of tumor cell biology. -
From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms: the Silent Way of Cancer Progression
biology Review From Clonal Hematopoiesis to Therapy-Related Myeloid Neoplasms: The Silent Way of Cancer Progression Carmelo Gurnari 1,2,3 , Emiliano Fabiani 1,4,* , Giulia Falconi 1 , Serena Travaglini 1 , Tiziana Ottone 1,5, Antonio Cristiano 1 and Maria Teresa Voso 1,5 1 Department of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, Italy; [email protected] (C.G.); [email protected] (G.F.); [email protected] (S.T.); [email protected] (T.O.); [email protected] (A.C.); [email protected] (M.T.V.) 2 Immunology, Molecular Medicine and Applied Biotechnology, University of Rome Tor Vergata, 00133 Rome, Italy 3 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA 4 Saint Camillus International, University of Health Sciences, 00131 Rome, Italy 5 Laboratorio di Neuro-Oncoematologia, Fondazione Santa Lucia, 00179 Rome, Italy * Correspondence: [email protected] Simple Summary: In the last decades the improved management of cancer patients and the overall prolonged life expectancy contributed to the increased number of patients at risk of late clonal events such as therapy-related myeloid neoplasms (t-MN). The discovery of clonal hematopoiesis of indeterminate potential (CHIP) in normal individuals has shed light on the pathophysiologic mecha- nism behind the process of myeloid evolution, defining CHIP carriers at higher risk of progression. Moreover, different patterns of clonal evolution have been identified in case of t-MN development after anti-cancer treatment exposure. The growing body of evidence in this field allowed the creation Citation: Gurnari, C.; Fabiani, E.; of dedicated cancer survivorship programs and “CHIP-Clinics” in order to specifically address the Falconi, G.; Travaglini, S.; Ottone, T.; issue of CHIP in patients undergoing anti-cancer treatment and develop measure of early detection Cristiano, A.; Voso, M.T. -
DNA Damage Checkpoint Dynamics Drive Cell Cycle Phase Transitions
bioRxiv preprint doi: https://doi.org/10.1101/137307; this version posted August 4, 2017. 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 4.0 International license. DNA damage checkpoint dynamics drive cell cycle phase transitions Hui Xiao Chao1,2, Cere E. Poovey1, Ashley A. Privette1, Gavin D. Grant3,4, Hui Yan Chao1, Jeanette G. Cook3,4, and Jeremy E. Purvis1,2,4,† 1Department of Genetics 2Curriculum for Bioinformatics and Computational Biology 3Department of Biochemistry and Biophysics 4Lineberger Comprehensive Cancer Center University of North Carolina, Chapel Hill 120 Mason Farm Road Chapel Hill, NC 27599-7264 †Corresponding Author: Jeremy Purvis Genetic Medicine Building 5061, CB#7264 120 Mason Farm Road Chapel Hill, NC 27599-7264 [email protected] ABSTRACT DNA damage checkpoints are cellular mechanisms that protect the integrity of the genome during cell cycle progression. In response to genotoxic stress, these checkpoints halt cell cycle progression until the damage is repaired, allowing cells enough time to recover from damage before resuming normal proliferation. Here, we investigate the temporal dynamics of DNA damage checkpoints in individual proliferating cells by observing cell cycle phase transitions following acute DNA damage. We find that in gap phases (G1 and G2), DNA damage triggers an abrupt halt to cell cycle progression in which the duration of arrest correlates with the severity of damage. However, cells that have already progressed beyond a proposed “commitment point” within a given cell cycle phase readily transition to the next phase, revealing a relaxation of checkpoint stringency during later stages of certain cell cycle phases. -
Characterization of BRCA1-Deficient Premalignant Tissues and Cancers Identifies Plekha5 As a Tumor Metastasis Suppressor
ARTICLE https://doi.org/10.1038/s41467-020-18637-9 OPEN Characterization of BRCA1-deficient premalignant tissues and cancers identifies Plekha5 as a tumor metastasis suppressor Jianlin Liu1,2, Ragini Adhav1,2, Kai Miao1,2, Sek Man Su1,2, Lihua Mo1,2, Un In Chan1,2, Xin Zhang1,2, Jun Xu1,2, Jianjie Li1,2, Xiaodong Shu1,2, Jianming Zeng 1,2, Xu Zhang1,2, Xueying Lyu1,2, Lakhansing Pardeshi1,3, ✉ ✉ Kaeling Tan1,3, Heng Sun1,2, Koon Ho Wong 1,3, Chuxia Deng 1,2 & Xiaoling Xu 1,2 1234567890():,; Single-cell whole-exome sequencing (scWES) is a powerful approach for deciphering intra- tumor heterogeneity and identifying cancer drivers. So far, however, simultaneous analysis of single nucleotide variants (SNVs) and copy number variations (CNVs) of a single cell has been challenging. By analyzing SNVs and CNVs simultaneously in bulk and single cells of premalignant tissues and tumors from mouse and human BRCA1-associated breast cancers, we discover an evolution process through which the tumors initiate from cells with SNVs affecting driver genes in the premalignant stage and malignantly progress later via CNVs acquired in chromosome regions with cancer driver genes. These events occur randomly and hit many putative cancer drivers besides p53 to generate unique genetic and pathological features for each tumor. Upon this, we finally identify a tumor metastasis suppressor Plekha5, whose deficiency promotes cancer metastasis to the liver and/or lung. 1 Cancer Centre, Faculty of Health Sciences, University of Macau, Macau, SAR, China. 2 Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Metabolic Checkpoints in Cancer Cell Cycle
City University of New York (CUNY) CUNY Academic Works All Dissertations, Theses, and Capstone Projects Dissertations, Theses, and Capstone Projects 2-2014 Metabolic Checkpoints in Cancer Cell Cycle Mahesh Saqcena Graduate Center, City University of New York How does access to this work benefit ou?y Let us know! More information about this work at: https://academicworks.cuny.edu/gc_etds/106 Discover additional works at: https://academicworks.cuny.edu This work is made publicly available by the City University of New York (CUNY). Contact: [email protected] METABOLIC CHECKPOINTS IN CANCER CELL CYCLE By Mahesh Saqcena A dissertation submitted to the Graduate Faculty in Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy, The City University of New York 2014 i 2014 Mahesh Saqcena All Rights Reserved ii This manuscript has been read and accepted for the Graduate Faculty in Biochemistry in satisfaction of the dissertation requirement for the degree of Doctor of Philosophy. Date Dr. David A. Foster (Chair of Examining Committee) Date Dr. Edward J. Kennelly (Executive Officer) Dr. Mitchell Goldfarb (Hunter College) Dr. Paul Feinstein (Hunter College) Dr. Richard Kolesnick (Sloan Kettering Institute) Dr. Frederick R. Cross (Rockefeller University) (Supervisory Committee) THE CITY UNIVERSITY OF NEW YORK iii Abstract METABOLIC CHECKPOINTS IN CANCER CELL CYCLE by Mahesh Saqcena Advisor: Dr. David A. Foster Growth factors (GFs) as well as nutrient sufficiency regulate cell division in metazoans. The vast majority of mutations that contribute to cancer are in genes that regulate progression through the G1 phase of the cell cycle. A key regulatory site in G1 is the growth factor-dependent Restriction Point (R), where cells get permissive signals to divide. -
Mitosis Vs. Meiosis
Mitosis vs. Meiosis In order for organisms to continue growing and/or replace cells that are dead or beyond repair, cells must replicate, or make identical copies of themselves. In order to do this and maintain the proper number of chromosomes, the cells of eukaryotes must undergo mitosis to divide up their DNA. The dividing of the DNA ensures that both the “old” cell (parent cell) and the “new” cells (daughter cells) have the same genetic makeup and both will be diploid, or containing the same number of chromosomes as the parent cell. For reproduction of an organism to occur, the original parent cell will undergo Meiosis to create 4 new daughter cells with a slightly different genetic makeup in order to ensure genetic diversity when fertilization occurs. The four daughter cells will be haploid, or containing half the number of chromosomes as the parent cell. The difference between the two processes is that mitosis occurs in non-reproductive cells, or somatic cells, and meiosis occurs in the cells that participate in sexual reproduction, or germ cells. The Somatic Cell Cycle (Mitosis) The somatic cell cycle consists of 3 phases: interphase, m phase, and cytokinesis. 1. Interphase: Interphase is considered the non-dividing phase of the cell cycle. It is not a part of the actual process of mitosis, but it readies the cell for mitosis. It is made up of 3 sub-phases: • G1 Phase: In G1, the cell is growing. In most organisms, the majority of the cell’s life span is spent in G1. • S Phase: In each human somatic cell, there are 23 pairs of chromosomes; one chromosome comes from the mother and one comes from the father. -
Efficient Immune Cell Genome Engineering with Improved CRISPR Editing Tools
bioRxiv preprint doi: https://doi.org/10.1101/2020.02.13.947002; this version posted February 14, 2020. 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 4.0 International license. 1 Title: Efficient Immune Cell Genome Engineering with Improved CRISPR Editing Tools 2 3 Authors: 4 Waipan Chan1,*, Rachel A. Gottschalk1,4, Yikun Yao2, Joel L. Pomerantz3 & Ronald N. Germain1,* 5 6 Affiliation: 7 1Lymphocyte Biology Section, Laboratory of Immune System Biology, National Institute of Allergy 8 and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 9 2Molecular Development of the Immune System Section, Laboratory of Immune System Biology, 10 National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 11 20892 12 3Department of Biological Chemistry and Institute for Cell Engineering, The Johns Hopkins 13 University School of Medicine, Baltimore, MD 21205 14 4Current Address: Department of Immunology, University of Pittsburgh School of Medicine, 15 W1047 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261 16 17 *Corresponding authors: [email protected]; [email protected] 18 19 This work was supported by the Intramural Research Program of NIAID, NIH. 20 21 All animal experiments were done in accordance with the guidelines of the NIAID/NIH 22 Institutional Animal Care and Use Committee. 1 bioRxiv preprint doi: https://doi.org/10.1101/2020.02.13.947002; this version posted February 14, 2020. 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. -
Pathognomonic and Epistatic Genetic Alterations in B-Cell Non-Hodgkin
bioRxiv preprint doi: https://doi.org/10.1101/674259; this version posted June 19, 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. 1 Pathognomonic and epistatic genetic alterations in 2 B-cell non-Hodgkin lymphoma 3 4 Man Chun John Ma1¥, Saber Tadros1¥, Alyssa Bouska2, Tayla B. Heavican2, Haopeng Yang1, 5 Qing Deng1, Dalia Moore3, Ariz Akhter4, Keenan Hartert3, Neeraj Jain1, Jordan Showell1, 6 Sreejoyee Ghosh1, Lesley Street5, Marta Davidson5, Christopher Carey6, Joshua Tobin7, 7 Deepak Perumal8, Julie M. Vose9, Matthew A. Lunning9, Aliyah R. Sohani10, Benjamin J. 8 Chen11, Shannon Buckley12, Loretta J. Nastoupil1, R. Eric Davis1, Jason R. Westin1, Nathan H. 9 Fowler1, Samir Parekh8, Maher K. Gandhi7, Sattva S. Neelapu1, Douglas Stewart5, Javeed 10 Iqbal2, Timothy Greiner2, Scott J. Rodig13, Adnan Mansoor5, Michael R. Green1,14,15* 11 1Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD 12 Anderson Cancer Center, Houston, TX, USA; 2Department of Pathology and Microbiology, University of 13 Nebraska Medical Center, Omaha, NE, USA; 3Eppley Institute for Research in Cancer and Allied 14 Diseases, University of Nebraska Medical Center, Omaha, NE, USA; 4Department of Pathology and 15 Laboratory Medicine, University of Calgary, Calgary, AB, Canada; 5Section of Hematology, Department of 16 Medicine, University -
Hypoxia-Induced Downregulation of DUSP-2 Phosphatase Drives Colon
Author Manuscript Published OnlineFirst on June 26, 2017; DOI: 10.1158/0008-5472.CAN-16-2990 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Hypoxia-induced downregulation of DUSP-2 phosphatase drives colon cancer stemness Pei-Chi Hou1†, Yo-Hua Li1†, Shih-Chieh Lin2, Shau-Chieh Lin3, Jenq-Chang Lee3, Bo-Wen Lin3, Jing-Ping Liou5, Jang-Yang Chang6, Ching-Chuan Kuo4, Yi-Min Liu5, H. Sunny Sun1,7, and Shaw-Jenq Tsai1, 2* 1Institute of Basic Medical Sciences, 2Department of Physiology, 3Department of Surgery, 6Department of Internal Medicine, and 7Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101, Taiwan 4Institute of Biotechnology & Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan 5School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei 11031, Taiwan †: Co-first authors Running title: DUSP2 inhibits cancer stemness Key words: Hypoxia, Dual specificity phosphatase, Cancer Stem Cells, Histone Deacetylase Inihibitor, Prostaglandin E2 Conflict of Interest: The authors declare no potential conflicts of interest. Financial support: This work was supported by National Research Program for Biopharmaceuticals (NSC 101-2325-B-006-017), National Health Research Institute 1 Downloaded from cancerres.aacrjournals.org on September 27, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 26, 2017; DOI: 10.1158/0008-5472.CAN-16-2990 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. (NHRI-EX-102-10244BI), and Top University grant of National Cheng Kung University (D103-35A17). -
Targeting the WEE1 Kinase As a Molecular Targeted Therapy for Gastric Cancer
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 31 Research Paper Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer Hye-Young Kim1,2, Yunhee Cho1,3, HyeokGu Kang1,3, Ye-Seal Yim1,3, Seok-Jun Kim1,3, Jaewhan Song2, Kyung-Hee Chun1,3 1Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seodaemun-gu, Seoul 03722, Korea 2Department of Biochemistry, College of Life Science and Biotechnology, Seodaemun-gu, Seoul 03722, Korea 3Brain Korea 21 PlusProject for Medical Science, Yonsei University, Seodaemun-gu, Seoul 03722, Korea Correspondence to: Kyung-Hee Chun, email: [email protected] Keywords: WEE1, AZD1775 (MK-1775), 5-FU, Paclitaxel, gastric cancer Received: September 07, 2015 Accepted: May 28, 2016 Published: June 23, 2016 ABSTRACT Wee1 is a member of the Serine/Threonine protein kinase family and is a key regulator of cell cycle progression. It has been known that WEE1 is highly expressed and has oncogenic functions in various cancers, but it is not yet studied in gastric cancers. In this study, we investigated the oncogenic role and therapeutic potency of targeting WEE1 in gastric cancer. At first, higher expression levels of WEE1 with lower survival probability were determined in stage 4 gastric cancer patients or male patients with accompanied lymph node metastasis. To determine the function of WEE1 in gastric cancer cells, we determined that WEE1 ablation decreased the proliferation, migration, and invasion, while overexpression of WEE1 increased these effects in gastric cancer cells. We also validated the clinical application of WEE1 targeting by a small molecule, AZD1775 (MK-1775), which is a WEE1 specific inhibitor undergoing clinical trials. -
The Cell Cycle & Mitosis
The Cell Cycle & Mitosis Cell Growth The Cell Cycle is G1 phase ___________________________________ _______________________________ During the Cell Cycle, a cell ___________________________________ ___________________________________ Anaphase Cell Division ___________________________________ Mitosis M phase M ___________________________________ S phase replication DNA Interphase Interphase is ___________________________ ___________________________________ G2 phase Interphase is divided into three phases: ___, ___, & ___ G1 Phase S Phase G2 Phase The G1 phase is a period of The S phase replicates During the G2 phase, many of activity in which cells _______ ________________and the organelles and molecules ____________________ synthesizes _______ molecules. required for ____________ __________ Cells will When DNA replication is ___________________ _______________ and completed, _____________ When G2 is completed, the cell is synthesize new ___________ ____________________ ready to enter the ____________________ ____________________ ____________________ ____________________ ____________________ Mitosis are divided into four phases: _____________, ______________, _____________, & _____________ Below are cells in two different phases of the cell cycle, fill in the blanks using the word bank: Chromatin Nuclear Envelope Chromosome Sister Chromatids Nucleolus Spinder Fiber Centrosome Centrioles 5.._________ 1.__________ v 6..__________ 2.__________ 7.__________ 3.__________ 8..__________ 4.__________ v The Cell Cycle & Mitosis Microscope Lab: