GADD45 Induction of a G2/M Cell Cycle Checkpoint
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Inhibition of Single Minded 2 Gene Expression Mediates Tumor-Selective Apoptosis and Differentiation in Human Colon Cancer Cells
Inhibition of Single Minded 2 gene expression mediates tumor-selective apoptosis and differentiation in human colon cancer cells Mireille J. Aleman*†‡§, Maurice Phil DeYoung*†§¶, Matthew Tress*†, Patricia Keating*†, Gary W. Perryʈ, and Ramaswamy Narayanan*†** *Center for Molecular Biology and Biotechnology, Departments of †Biology and ‡Chemistry, and ¶Center for Complex System and Brain Sciences, Florida Atlantic University, 777 Glades Road, Boca Raton, FL 33431 Communicated by Herbert Weissbach, Florida Atlantic University, Boca Raton, FL, July 21, 2005 (received for review April 4, 2005) A Down’s syndrome associated gene, Single Minded 2 gene short bound AhR͞ARNT complex (12) and hence prevent carcinogen form (SIM2-s), is specifically expressed in colon tumors but not in metabolism, leading to cumulative DNA damage and cancer. the normal colon. Antisense inhibition of SIM2-s in a RKO-derived The growth arrest and DNA damage (GADD) family of genes colon carcinoma cell line causes growth inhibition, apoptosis, and was originally isolated from UV radiation-treated cells and subse- inhibition of tumor growth in a nude mouse tumoriginicity model. quently grouped according to their coordinate regulation by growth The mechanism of cell death in tumor cells is unclear. In the present arrest and DNA damage (13). The GADD family members include study, we investigated the pathways underlying apoptosis. Apo- GADD34,-45␣,-45,-45␥, and -153 (14, 15). These are stress- ptosis was seen in a tumor cell-specific manner in RKO cells but not response genes induced by both genotoxic and nongenotoxic in normal renal epithelial cells, despite inhibition of SIM2-s expres- stresses (16–18). GADD45␣ is the most extensively studied mem- sion in both of these cells by the antisense. -
Genetic Deletion Ofgadd45b, a Regulator of Active DNA
The Journal of Neuroscience, November 28, 2012 • 32(48):17059–17066 • 17059 Brief Communications Genetic Deletion of gadd45b, a Regulator of Active DNA Demethylation, Enhances Long-Term Memory and Synaptic Plasticity Faraz A. Sultan,1 Jing Wang,1 Jennifer Tront,2 Dan A. Liebermann,2 and J. David Sweatt1 1Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294 and 2Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, Pennsylvania 19140 Dynamic epigenetic mechanisms including histone and DNA modifications regulate animal behavior and memory. While numerous enzymes regulating these mechanisms have been linked to memory formation, the regulation of active DNA demethylation (i.e., cytosine-5 demethylation) has only recently been investigated. New discoveries aim toward the Growth arrest and DNA damage- inducible 45 (Gadd45) family, particularly Gadd45b, in activity-dependent demethylation in the adult CNS. This study found memory- associated expression of gadd45b in the hippocampus and characterized the behavioral phenotype of gadd45b Ϫ/Ϫ mice. Results indicate normal baseline behaviors and initial learning but enhanced persisting memory in mutants in tasks of motor performance, aversive conditioning and spatial navigation. Furthermore, we showed facilitation of hippocampal long-term potentiation in mutants. These results implicate Gadd45b as a learning-induced gene and a regulator of memory formation and are consistent with its potential role in active DNA demethylation in memory. Introduction along with the finding of activity-induced gadd45b in the hip- Alterations in neuronal gene expression play a necessary role pocampus led us to hypothesize that Gadd45b modulates mem- in memory consolidation (Miyashita et al., 2008). -
Gadd45a Regulates B-Catenin Distribution and Maintains Cell–Cell Adhesion/ Contact
Oncogene (2007) 26, 6396–6405 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc ORIGINAL ARTICLE Gadd45a regulates b-catenin distribution and maintains cell–cell adhesion/ contact JJi1, R Liu1, T Tong, Y Song, S Jin, M Wu and Q Zhan State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, PR China Gadd45a,a growth arrest and DNA-damage gene,plays 1999;Jin et al., 2000;Tong et al., 2005). Gadd45a important roles in the control of cell cycle checkpoints, also plays roles in negative regulation of cell malig- DNA repair and apoptosis. We show here that Gadd45a is nancy. Mouse embryonic fibroblasts (MEFs) derived involved in the control of cell contact inhibition and cell– from Gadd45a-null mice exhibited genomic instability, cell adhesion. Gadd45a can serve as an adapter to enhance single oncogene-mediated transformation, loss of nor- the interaction between b-catenin and Caveolin-1,and in mal cellular senescence, increased cellular proliferation, turn induces b-catenin translocation to cell membrane for centrosome amplification and reduced DNA repair maintaining cell–cell adhesion/contact inhibition. This is (Hollander et al., 1999;Smith et al., 2000). Gadd45a- coupled with reduction of b-catenin in cytoplasm and null mice have an increased frequency of tumorigenesis nucleus following Gadd45a induction,which is reflected by by ionizing radiation (IR), ultraviolet radiation (UVR) the downregulation of cyclin D1,one of the b-catenin and dimethylbenzanthracene (DMBA), although these targeted genes. Additionally,Gadd45a facilitates ultra- mice do not develop spontaneous tumors (Hollander violet radiation-induced degradation of cytoplasmic and et al., 1999, 2001;Hildesheim et al., 2002). -
DNA Excision Repair Proteins and Gadd45 As Molecular Players for Active DNA Demethylation
Cell Cycle ISSN: 1538-4101 (Print) 1551-4005 (Online) Journal homepage: http://www.tandfonline.com/loi/kccy20 DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation Dengke K. Ma, Junjie U. Guo, Guo-li Ming & Hongjun Song To cite this article: Dengke K. Ma, Junjie U. Guo, Guo-li Ming & Hongjun Song (2009) DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation, Cell Cycle, 8:10, 1526-1531, DOI: 10.4161/cc.8.10.8500 To link to this article: http://dx.doi.org/10.4161/cc.8.10.8500 Published online: 15 May 2009. Submit your article to this journal Article views: 135 View related articles Citing articles: 92 View citing articles Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=kccy20 Download by: [University of Pennsylvania] Date: 27 April 2017, At: 12:48 [Cell Cycle 8:10, 1526-1531; 15 May 2009]; ©2009 Landes Bioscience Perspective DNA excision repair proteins and Gadd45 as molecular players for active DNA demethylation Dengke K. Ma,1,2,* Junjie U. Guo,1,3 Guo-li Ming1-3 and Hongjun Song1-3 1Institute for Cell Engineering; 2Department of Neurology; and 3The Solomon Snyder Department of Neuroscience; Johns Hopkins University School of Medicine; Baltimore, MD USA Abbreviations: DNMT, DNA methyltransferases; PGCs, primordial germ cells; MBD, methyl-CpG binding protein; NER, nucleotide excision repair; BER, base excision repair; AP, apurinic/apyrimidinic; SAM, S-adenosyl methionine Key words: DNA demethylation, Gadd45, Gadd45a, Gadd45b, Gadd45g, 5-methylcytosine, deaminase, glycosylase, base excision repair, nucleotide excision repair DNA cytosine methylation represents an intrinsic modifica- silencing of gene activity or parasitic genetic elements (Fig. -
Spatiotemporal Expression Pattern of Gadd45g Signaling Pathway
Metab y & o g lic lo S o y n n i r d Labrie et al. Endocrinol Metabol Syndrome 2011, S:4 c r o o m d n e DOI: 10.4172/2161-1017.S4-005 E Endocrinology & Metabolic Syndrome ISSN: 2161-1017 Research Article Open Access Spatiotemporal Expression Pattern of Gadd45g Signaling Pathway Components in the Mouse Uterus Following Hormonal Steroid Treatments Yvan Labrie, Karine Plourde, Johanne Ouellet, Geneviève Ouellette, Céline Martel, Fernand Labrie, Georges Pelletier and Francine Durocher* Oncology and Molecular Endocrinology Research Centre, CHUQ Research Centre, CHUL, Department of Molecular Medicine, Laval University, Québec, G1V 4G2, Canada Abstract The uterus is a hormone-dependent organ under the control of estrogens, progestins and androgens. The actions of estradiol (E2) and progesterone on uterine physiology are well documented, while active androgens such as testosterone and dihydrotestosterone (DHT) are now also recognized to exert an important role to appropriately maintain the cyclical changes of the endometrium. Based on our previous observations that DHT modulates GADD45g and the expression of specific cell cycle genes, the aim of this study was to identify the specific uterine cell types in which these cell cycle genes are modulated by hormonal steroids. Using in situ hybridization and quantitative RT-PCR (QRT-PCR), the localization and measurement of mRNA expression of key cell cycle genes responding to E2 and DHT were performed in the uterus of ovariectomized mice. Interestingly, in situ hybridization experiments demonstrate that Gadd45g mRNA is detected early and strongly in stromal cells only, indicating that the early cell cycle arrest induced by DHT and E2 in the mouse uterus occurs in this compartment. -
GADD45 Regulates Hepatic Gluconeogenesis Via Modulating
biomedicines Article GADD45β Regulates Hepatic Gluconeogenesis via Modulating the Protein Stability of FoxO1 Hyunmi Kim 1,2 , Da Som Lee 1,2 , Tae Hyeon An 1,2 , Tae-Jun Park 1, Eun-Woo Lee 1 , Baek Soo Han 1,2, Won Kon Kim 1,2, Chul-Ho Lee 3 , Sang Chul Lee 1,2, Kyoung-Jin Oh 1,2,* and Kwang-Hee Bae 1,2,* 1 Metabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; [email protected] (H.K.); [email protected] (D.S.L.); [email protected] (T.H.A.); [email protected] (T.-J.P.); [email protected] (E.-W.L.); [email protected] (B.S.H.); [email protected] (W.K.K.); [email protected] (S.C.L.) 2 Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology (UST), Daejeon 34141, Korea 3 Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea; [email protected] * Correspondence: [email protected] (K.-J.O.); [email protected] (K.-H.B.) Abstract: Increased hepatic gluconeogenesis is one of the main contributors to the development of type 2 diabetes. Recently, it has been reported that growth arrest and DNA damage-inducible 45 beta (GADD45β) is induced under both fasting and high-fat diet (HFD) conditions that stimulate hepatic gluconeogenesis. Here, this study aimed to establish the molecular mechanisms under- lying the novel role of GADD45β in hepatic gluconeogenesis. Both whole-body knockout (KO) mice and adenovirus-mediated knockdown (KD) mice of GADD45β exhibited decreased hepatic gluconeogenic gene expression concomitant with reduced blood glucose levels under fasting and HFD conditions, but showed a more pronounced effect in GADD45β KD mice. -
Role of D-GADD45 in JNK-Dependent Apoptosis and Regeneration in Drosophila
G C A T T A C G G C A T genes Article Role of D-GADD45 in JNK-Dependent Apoptosis and Regeneration in Drosophila Carlos Camilleri-Robles, Florenci Serras and Montserrat Corominas * Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona 08028, Spain; [email protected] (C.C.-R.); [email protected] (F.S.) * Correspondence: [email protected] Received: 28 March 2019; Accepted: 16 May 2019; Published: 18 May 2019 Abstract: The GADD45 proteins are induced in response to stress and have been implicated in the regulation of several cellular functions, including DNA repair, cell cycle control, senescence, and apoptosis. In this study, we investigate the role of D-GADD45 during Drosophila development and regeneration of the wing imaginal discs. We find that higher expression of D-GADD45 results in JNK-dependent apoptosis, while its temporary expression does not have harmful effects. Moreover, D-GADD45 is required for proper regeneration of wing imaginal discs. Our findings demonstrate that a tight regulation of D-GADD45 levels is required for its correct function both, in development and during the stress response after cell death. Keywords: GADD45; JNK; p38; development; regeneration; imaginal discs 1. Introduction The Growth Arrest and DNA Damage-inducible 45 (GADD45) family of proteins acts as stress sensors in response to various stimuli. The first GADD45 gene was identified in mammals on the basis of its increased expression after growth cessation signals or treatment with DNA-damaging agents [1,2]. This gene, renamed as GADD45α, is a member of a highly conserved family, together with GADD45β and GADD45γ. -
Recombinant Human Adenovirus-P53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: a Systematic Review
medicina Review Recombinant Human Adenovirus-p53 Therapy for the Treatment of Oral Leukoplakia and Oral Squamous Cell Carcinoma: A Systematic Review Jagadish Hosmani 1 , Shazia Mushtaq 2, Shahabe Saquib Abullais 3, Hussain Mohammed Almubarak 1, Khalil Assiri 1, Luca Testarelli 4 , Alessandro Mazzoni 4 and Shankargouda Patil 5,* 1 Department of Diagnostic Dental Sciences, College of Dentistry, King Khalid University, Abha 62529, Saudi Arabia; [email protected] (J.H.); [email protected] (H.M.A.); [email protected] (K.A.) 2 Dental Health Department, College of Applied Medical Sciences, King Saud University, Riyadh 11451, Saudi Arabia; [email protected] 3 Periodontics and Community Dental Sciences, College of Dentistry, King Khalid University, Abha 62529, Saudi Arabia; [email protected] 4 Department of Oral and Maxillo Facial Sciences, Sapienza University of Rome, 00185 Rome, Italy; [email protected] (L.T.); [email protected] (A.M.) 5 Department of Maxillofacial Surgery and Diagnostic Sciences, Division of oral Pathology, College of Dentistry, Jazan University, Jazan 45142, Saudi Arabia * Correspondence: [email protected] Abstract: Background and Objectives: Oral cancer is the 6th most common cancer in the world and Citation: Hosmani, J.; Mushtaq, S.; oral leukoplakia is an oral potentially malignant disorder that could develop into oral cancer. This Abullais, S.S.; Almubarak, H.M.; systematic review focusses on randomized clinical trials for recombinant adenovirus p-53 (rAD-p53) Assiri, K.; Testarelli, L.; Mazzoni, A.; therapy for the treatment of oral leukoplakia and cancer. Materials and Methods: We searched for Patil, S. Recombinant Human research articles on various databases such as Pubmed/Medline, Embase, CNKI (China National Adenovirus-p53 Therapy for the Knowledge Infra-structure), Springerlink, cochrane and Web of sciences from 2003 to 2020. -
Regulation of Stress-Activated Map Kinase Pathways During Cell Fate Decisions
INVITED REVIEW ARTICLE Nagoya J. Med. Sci. 73. 1 ~ 14, 2011 REGULATION OF STRESS-ACTIVATED MAP KINASE PATHWAYS DURING CELL FATE DECISIONS MUTSUHIRO TAKEKAWA, YUJI KUBOTA, TAKANORI NAKAMURA and KENJI ICHIKAWA Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University ABSTRACT Mammalian cells are frequently exposed to a variety of environmental stresses, such as ultraviolet rays, ionizing radiation, genotoxins, heat shock, and oxidative stress. In coping with the barrage of these and other stresses, multi-cellular eukaryotic organisms have developed a strategy as to how damaged cells will respond to stresses. In general, if the intensity of the damage is moderate, the cell will seek to repair the damage. If, however, the damage to a cell is too severe to be repaired, the affected cells are eliminated by apoptosis. This cell death reduces the risk to the organism as a whole, such as development of a cancer. Such a crucial decision between survival and death is, at least in part, mediated by the stress-activated MAP kinase (SAPK) pathways. SAPKs are a group of serine/threonine protein kinases that convert extracellular stress stimuli into diverse cellular responses, including cell cycle arrest, apoptotic cell death, and cytokine production, through phosphorylation of specific target proteins. Recent progress in the identification of molecules that participate in the SAPK pathways, such as GADD45 proteins and Wip1, has provided new insights, not only into the molecular basis of the -
The P38 Pathway: from Biology to Cancer Therapy
International Journal of Molecular Sciences Review The p38 Pathway: From Biology to Cancer Therapy 1,2, 1,2, 1,2, 1,2, Adrián Martínez-Limón y, Manel Joaquin y, María Caballero y , Francesc Posas * and Eulàlia de Nadal 1,2,* 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac, 10, 08028 Barcelona, Spain; [email protected] (A.M.-L.); [email protected] (M.J.); [email protected] (M.C.) 2 Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), E-08003 Barcelona, Spain * Correspondence: [email protected] (F.P.); [email protected] (E.d.N.); Tel.: +34-93-403-4810 (F.P.); +34-93-403-9895 (E.d.N.) These authors contributed equally to this work. y Received: 29 January 2020; Accepted: 9 March 2020; Published: 11 March 2020 Abstract: The p38 MAPK pathway is well known for its role in transducing stress signals from the environment. Many key players and regulatory mechanisms of this signaling cascade have been described to some extent. Nevertheless, p38 participates in a broad range of cellular activities, for many of which detailed molecular pictures are still lacking. Originally described as a tumor-suppressor kinase for its inhibitory role in RAS-dependent transformation, p38 can also function as a tumor promoter, as demonstrated by extensive experimental data. This finding has prompted the development of specific inhibitors that have been used in clinical trials to treat several human malignancies, although without much success to date. However, elucidating critical aspects of p38 biology, such as isoform-specific functions or its apparent dual nature during tumorigenesis, might open up new possibilities for therapy with unexpected potential. -
Myc Suppresses Induction of the Growth Arrest Genes Gadd34, Gadd45, and Gadd153 by DNA-Damaging Agents
Oncogene (1998) 17, 2149 ± 2154 ã 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Myc suppresses induction of the growth arrest genes gadd34, gadd45, and gadd153 by DNA-damaging agents SA Amundson1, Q Zhan1, LZ Penn2 and AJ Fornace Jr1 1NCI, NIH, Bethesda, Maryland 20892, USA; 2Department of Medical Biophysics, University of Toronto, Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada The growth arrest and DNA damage inducible (gadd) transcription of the gadd genes regardless of p53 genes are induced by various genotoxic and non- status in all mammalian cells examined (Kastan et genotoxic stresses such as serum starvation, ultraviolet al., 1992). Despite the inability of p53 to transactivate irradiation and treatment with alkylating agents. Their a gadd45 promoter-reporter construct (Zhan et al., coordinate induction is a growth arrest signal which may 1993), p53 still appears to play some role in the stress- play an important role in the response of cells to DNA responsiveness of the promoter (Zhan et al., 1998), damage. Conversely, c-myc is a strong proliferative consistent with the decreased response of gadd45 and signal, and overexpression of Myc is frequently observed gadd153 to UV radiation and MMS observed in p53- in cancer cells. We have found that ectopic expression of null mouse embryo ®broblasts and in human cancer v-myc in RAT-1 cells results in an attenuated induction cell lines with p53 function abrogated by dominant- of the three major gadd transcripts by methyl negative vectors (Zhan et al., 1996). -
Journal of Molecular Signaling Biomed Central
Journal of Molecular Signaling BioMed Central Review Open Access Gadd45 in stress signaling Dan A Liebermann* and Barbara Hoffman Address: Fels Institute for Cancer Research & Molecular Biology, & Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA Email: Dan A Liebermann* - [email protected]; Barbara Hoffman - [email protected] * Corresponding author Published: 12 September 2008 Received: 22 July 2008 Accepted: 12 September 2008 Journal of Molecular Signaling 2008, 3:15 doi:10.1186/1750-2187-3-15 This article is available from: http://www.jmolecularsignaling.com/content/3/1/15 © 2008 Liebermann and Hoffman; 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 Gadd45 genes have been implicated in stress signaling in response to physiological or environmental stressors, which results in cell cycle arrest, DNA repair, cell survival and senescence, or apoptosis. Evidence accumulated implies that Gadd45 proteins function as stress sensors is mediated by a complex interplay of physical interactions with other cellular proteins that are implicated in cell cycle regulation and the response of cells to stress. These include PCNA, p21, cdc2/cyclinB1, and the p38 and JNK stress response kinases. What deterministic factors dictate whether Gadd45 and partner proteins function in either cell survival or apoptosis remains to be determined. An attractive working model to consider is that the extent of cellular/DNA damage, in a given cell type, dictates the association of different Gadd45 proteins with particular partner proteins, which determines the outcome.