Control of Cell Cycle Progression by C-Jun Is P53 Dependent
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Wild-Type P53 Can Down-Modulate the Activity of Various Promoters
Proc. Natl. Acad. Sci. USA Vol. 88, pp. 9979-9983, November 1991 Biochemistry Wild-type p53 can down-modulate the activity of various promoters DORON GINSBERG*, FATIMA MECHTAt, MOSHE YANIVt, AND MOSHE OREN*t *Department of Chemical Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel; and tDepartment of Biotechnology, Pasteur Institute, 75724 Paris Cedex 15, France Communicated by Robert A. Weinberg, August 16, 1991 ABSTRACT The wild-type (wt) p53 protein is the product out whether it could also modulate c-fos expression. We of a tumor suppressor gene that is a frequent target for report here that wt p53 can inhibit c-fos gene expression. This inactivation in many types of tumors. The nuclear localization effect of wt p53 is rapid, suggesting that it may precede ofthe protein, as well as additional features, suggest that it may growth arrest. In addition, cotransfection experiments indi- be involved in the regulation ofgene expression. To explore this cate that wt p53 can down-modulate the activity of a number possibility, the effects of overproduced wt p53 were investi- of promoters. While the effect of wt p53 appeared to be gated in a number of systems. Induction of growth arrest via relatively nonspecific, it probably did not reflect a general- the antiproliferative effect ofwt p53 greatly impaired the ability ized transcriptional shut-off. Our findings suggest that wt p53 of cells to exhibit an increase in c-fos mRNA upon serum may contribute to growth inhibition by down-modulating, stimulation. Experiments in which cells were cotransfected directly or indirectly, the expression of genes that are re- with p53 expression plasmids together with a reporter gene quired for ongoing cell proliferation. -
Retinoblastoma Protein Positively Regulates Terminal Adipocyte Differentiation Through Direct Interaction with C/Ebps
Downloaded from genesdev.cshlp.org on October 3, 2021 - Published by Cold Spring Harbor Laboratory Press Retinoblastoma protein positively regulates terminal adipocyte differentiation through direct interaction with C/EBPs Phang-Lang Chen, Daniel J. Riley, Yumay Chen, and Wen-Hwa Lee l Center for Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245 USA To define a mechanism by which retinoblastoma protein (Rb) functions in cellular differentiation, we studied primary fibroblasts from the lung buds of wild-type (RB + / +) and null-mutant (RB-/-) mouse embryos. In culture, the RB +/+ fibroblasts differentiated into fat-storing cells, either spontaneously or in response to hormonal induction; otherwise syngenic RB -/- fibroblasts cultured in identical conditions did not. Ectopic expression of normal Rb, but not Rb with a single point mutation, enabled RB-/- fibroblasts to differentiate into adipocytes. Rb appears in murine fibroblasts to activate CCAAT/enhancer-binding proteins (C/EBPs), a family of transcription factors crucial for adipocyte differentiation. Physical interaction between Rb and C/EBPs was demonstrated by reciprocal coimmunoprecipitation, but occurred only in differentiating cells. Wild-type Rb also enhanced the binding of C/EBP to cognate DNA sequences in vitro and the transact[vat[on of a C/EBPl$-responsive promoter in cells. Taken together, these observations establish a direct and positive role for Rb in terminal differentiation. Such a role contrasts with the function of Rb in arresting cell cycle progression in G1 by negative regulation of other transcription factors like E2F-1. [Key Words: C/EBP; transcription factors; cell cycle; adipocyte differentiation; tumor suppressor protein] Received July 18, 1996; revised version accepted September 5, 1996. -
Original Article Regulation of Exogenous P53 Combined with Dickkopf-1 on Human Osteosarcoma MG-63 Cells
Int J Clin Exp Med 2017;10(6):9252-9258 www.ijcem.com /ISSN:1940-5901/IJCEM0052476 Original Article Regulation of exogenous P53 combined with Dickkopf-1 on human osteosarcoma MG-63 cells Fuyu Gao, Benjun Bi, Guangjun Liao Department of Orthopedic Surgery, Yantaishan Hospital, Yantai, Shandong, China Received March 8, 2017; Accepted April 22, 2017; Epub June 15, 2017; Published June 30, 2017 Abstract: Objective: To regulate the growth of human osteosarcoma cell strain MG-63 in vitro through the combined drugs of exogenous P53 gene and Dickkopf-1 and to explore its possible mechanisms in order to provide the refer- ence for clinical treatment of osteosarcoma. Methods: Human osteosarcoma MG-63 cell strain was subcultured in vitro, and exogenous P53 and Dickkopf-1 were used separately or jointly to act on MG-63 cells. The proliferation and apoptosis of MG-63 cells were respectively detected by trypan blue exclusion and flow cytometry; the expres- sion levels of tumor suppressor gene P53 and oncogene c-fos and c-myc were detected by real-time fluorescent quantitative and western blot in mRNA and protein levels. Results: The proliferation test results showed that the combination of exogenous P53 and Dickkopf-1 could significantly inhibit the growth of MG-63 cells, compared with the single drug using (P<0.05), and cell cycle assay found that the combined drugs caused the cell cycle arrest at G0/G1 phase (P<0.05). Flow cytometry assay indicated the apoptosis of MG-63 cells caused by the combined drugs was significantly higher than that of using exogenous P53 or Dickkopf-1 alone, and the results of western blot manifested the combined drugs could down-regulate the expression levels of c-fos and c-myc whichwere related to the proliferation and differentiation of MG-63 cells, and increase the expression of tumor suppressor gene P53. -
Carcinogeninduced Hepatic Tumors in KLF6+/ Mice Recapitulate
HEPATOBILIARY MALIGNANCIES Carcinogen-Induced Hepatic Tumors in KLF61/2 Mice Recapitulate Aggressive Human Hepatocellular Carcinoma Associated with p53 Pathway Deregulation Mirko Tarocchi,1,2 Rebekka Hannivoort,1,3 Yujin Hoshida,4 Ursula E. Lee,1 Diana Vetter,1 Goutham Narla,5,6 Augusto Villanueva,7,8 Moshe Oren,8 Josep M. Llovet,1,7,9 and Scott L. Friedman1 Inactivation of KLF6 is common in hepatocellular carcinoma (HCC) associated with hepa- titis C virus (HCV) infection, thereby abrogating its normal antiproliferative activity in liver cells. The aim of the study was to evaluate the impact of KLF6 depletion on human HCC and experimental hepatocarcinogenesis in vivo. In patients with surgically resected HCC, reduced tumor expression of KLF6 was associated with decreased survival. Consistent with its role as a tumor suppressor, KLF61/2 mice developed significantly more tumors in response to the chemical carcinogen diethyl nitrosamine (DEN) than wild-type animals. Gene expression signatures in both surrounding tissue and tumors of KLF61/2 mice closely recapitulated those associated with aggressive human HCCs. Expression microarray profiling also revealed an increase in Mdm2 mRNA in tumors from KLF61/2 compared with KLF61/1 mice, which was validated by way of quantitative real-time polymerase chain reaction and western blot analysis in both human HCC and DEN-induced murine tumors. Moreover, chromatin immunoprecipitation and cotransfection assays established the P2 intronic promoter of Mdm2 as a bona fide transcriptional target repressed by KLF6. Whereas KLF6 overexpression in HCC cell lines and primary hepatocytes led to reduced MDM2 levels and increased p53 protein and transcriptional activity, reduction in KLF6 by small interfering RNA led to increased MDM2 and reduced p53. -
Teacher Background on P53 Tumor Suppressor Protein
Cancer Lab p53 – Teacher Background on p53 Tumor Suppressor Protein Note: The Teacher Background Section is meant to provide information for the teacher about the topic and is tied very closely to the PowerPoint slide show. For greater understanding, the teacher may want to play the slide show as he/she reads the background section. For the students, the slide show can be used in its entirety or can be edited as necessary for a given class. What Is p53 and Where Is the Gene Located? While commonly known as p53, the official name of this gene is Tumor Protein p53 and its official symbol is TP53. TheTP53 gene codes for the TP53 (p53) protein which acts as a tumor suppressor and works in response to DNA damage to orchestrate the repair of damaged DNA. If the DNA cannot be repaired, the p53 protein prevents the cell from dividing and signals it to undergo apoptosis (programmed cell death). The name p53 is due to protein’s 53 kilo-Dalton molecular mass. The gene which codes for this protein is located on the short (p) arm of chromosome 17 at position 13.1 (17p13.1). The gene begins at base pair 7,571,719 and ends at base pair 7, 590,862 making it 19,143 base pairs long. (1, 2) What Does the p53 Gene Look Like When Translated Into Protein? The TP53 gene has 11 exons and a very large 10 kb intron between exons 1 and 2. In humans, exon 1 is non-coding and it has been shown that this region could form a stable stem-loop structure which binds tightly to normal p53 but not to mutant p53 proteins. -
Nuclear Localization of DP and E2F Transcription Factors by Heterodimeric Partners and Retinoblastoma Protein Family Members
Journal of Cell Science 109, 1717-1726 (1996) 1717 Printed in Great Britain © The Company of Biologists Limited 1996 JCS7086 Nuclear localization of DP and E2F transcription factors by heterodimeric partners and retinoblastoma protein family members Junji Magae1, Chin-Lee Wu2, Sharon Illenye1, Ed Harlow2 and Nicholas H. Heintz1,* 1Department of Pathology, University of Vermont, Burlington VT 05405, USA 2Massachusetts General Hospital Cancer Center, Charlestown MA 02129, USA *Author for correspondence SUMMARY E2F is a family of transcription factors implicated in the showed that regions of E2F-1 and DP-1 that are required regulation of genes required for progression through G1 for stable association of the two proteins were also required and entry into the S phase. The transcriptionally active for nuclear localization of DP-1. Unlike E2F-1, -2, and -3, forms of E2F are heterodimers composed of one polypep- E2F-4 did not accumulate in the nucleus unless it was coex- tide encoded by the E2F gene family and one polypeptide pressed with DP-2. p107 and p130, but not pRb, stimulated encoded by the DP gene family. The transcriptional activity nuclear localization of E2F-4, either alone or in combina- of E2F/DP heterodimers is influenced by association with tion with DP-2. These results indicate that DP proteins the members of the retinoblastoma tumor suppressor preferentially associate with specific E2F partners, and protein family (pRb, p107, and p130). Here the intracellu- suggest that the ability of specific E2F/DP heterodimers to lar distribution of E2F and DP proteins was investigated in localize in the nucleus contributes to the regulation of E2F transiently transfected Chinese hamster and human cells. -
TP63 and TP73 in Cancer, an Unresolved В€Œfamily∕ Puzzle Of
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 588 (2014) 2590–2599 journal homepage: www.FEBSLetters.org Review TP63 and TP73 in cancer, an unresolved ‘‘family’’ puzzle of complexity, redundancy and hierarchy Antonio Costanzo a, Natalia Pediconi b,c, Alessandra Narcisi a, Francesca Guerrieri c,d, Laura Belloni c,d, ⇑ Francesca Fausti a, Elisabetta Botti a, Massimo Levrero c,d, a Dermatology Unit, Department of Neuroscience, Mental Health and Sensory Organs (NESMOS), Sapienza University of Rome, Italy b Laboratory of Molecular Oncology, Department of Molecular Medicine, Sapienza University of Rome, Italy c Center for Life Nanosciences (CNLS) – IIT/Sapienza, Rome, Italy d Laboratory of Gene Expression, Department of Internal Medicine (DMISM), Sapienza University of Rome, Italy article info abstract Article history: TP53 belongs to a small gene family that includes, in mammals, two additional paralogs, TP63 and Received 19 May 2014 TP73. The p63 and p73 proteins are structurally and functionally similar to p53 and their activity as Revised 16 June 2014 transcription factors is regulated by a wide repertoire of shared and unique post-translational mod- Accepted 16 June 2014 ifications and interactions with regulatory cofactors. p63 and p73 have important functions in Available online 28 June 2014 embryonic development and differentiation but are also involved in tumor suppression. The biology Edited by Shairaz Baksh, Giovanni Blandino of p63 and p73 is complex since both TP63 and TP73 genes are transcribed into a variety of different and Wilhelm Just isoforms that give rise to proteins with antagonistic properties, the TA-isoforms that act as tumor- suppressors and DN-isoforms that behave as proto-oncogenes. -
Jdp2 Downregulates Trp53 Transcription to Promote Leukaemogenesis in the Context of Trp53 Heterozygosity
Oncogene (2013) 32, 397 --402 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc SHORT COMMUNICATION Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity L van der Weyden1, AG Rust1,4, RE McIntyre1,4, CD Robles-Espinoza1, M del Castillo Velasco-Herrera1, R Strogantsev2, AC Ferguson-Smith2, S McCarthy1, TM Keane1, MJ Arends3 and DJ Adams1 We performed a genetic screen in mice to identify candidate genes that are associated with leukaemogenesis in the context of Trp53 heterozygosity. To do this we generated Trp53 heterozygous mice carrying the T2/Onc transposon and SB11 transposase alleles to allow transposon-mediated insertional mutagenesis to occur. From the resulting leukaemias/lymphomas that developed in these mice, we identified nine loci that are potentially associated with tumour formation in the context of Trp53 heterozygosity, including AB041803 and the Jun dimerization protein 2 (Jdp2). We show that Jdp2 transcriptionally regulates the Trp53 promoter, via an atypical AP-1 site, and that Jdp2 expression negatively regulates Trp53 expression levels. This study is the first to identify a genetic mechanism for tumour formation in the context of Trp53 heterozygosity. Oncogene (2013) 32, 397--402; doi:10.1038/onc.2012.56; published online 27 February 2012 Keywords: p53; Jdp2; transposon; heterozygosity; lymphoma; mice INTRODUCTION targeted by transposon insertion events leading to upregulated Genetic alterations of TP53 are frequent events in tumourigenesis Jdp2 expression and a decrease in Trp53 expression levels. Further and promote genomic instability, impair apoptosis, and contribute we illustrate that Jdp2 regulates the Trp53 promoter via an atypical to aberrant self-renewal.1--4 The spectrum of mutations that occur AP-1 binding site. -
RB1 and P53 at the Crossroad of EMT and Triple Negative Breast Cancer
PERSPECTIVE PERSPECTIVE Cell Cycle 10:10, 1-8; May 15, 2011; © 2011 Landes Bioscience RB1 and p53 at the crossroad of EMT and triple negative breast cancer Zhe Jiang,1 Robert Jones,1 Jeff C. Liu,1 Tao Deng,1 Tyler Robinson,1 Philip E.D. Chung,1 Sharon Wang,1 Jason I. Herschkowitz,2 Sean E. Egan,3 Charles M. Perou4 and Eldad Zacksenhaus1,* 1Division of Cell and Molecular Biology; Toronto General Research Institute; University Health Network; Toronto, Ontario, Canada; 2Department of Molecular and Cellular Biology; Baylor College of Medicine; Houston, TX USA; 3Program in Developmental and Stem Cell Biology; The Hospital for Sick Children; Department of Molecular Genetics; University of Toronto; Toronto, Ontario, Canada; 4Lineberger Comprehensive Cancer Center; Department of Genetics and Pathology; University of North Carolina at Chapel Hill; Chapel Hill, NC USA riple negative breast cancer (TNBC) NEU-positive and Triple Negative (TN) Tis a heterogeneous disease that tumors, the latter of which do not express includes Basal-like and Claudin-low hormone receptors or HER2.1-7 TNBC tumors. The Claudin-low tumors are affects 15–30% of patients. By IHC it can enriched for features associated with be further divided into Basal-like breast epithelial-to-mesenchymal transition cancer and non-basal tumors, some of (EMT) and possibly for tumor initiating which exhibit features of EMT.8 Basal-like cells. Primary TNBCs respond relatively BCs express the basal cytokeratins (CK) well to conventional chemotherapy; CK5/6, CK14, CK17, and/or epidermal © 2011 Landes Bioscience. Landes ©2011 however, metastatic disease is virtually growth factor receptor (EGFR), whereas incurable. -
Crucial Role of C-Jun Phosphorylation at Ser63/73 Mediated by PHLPP Protein Degradation in the Cheliensisin a Inhibition of Cell Transformation
Published OnlineFirst October 3, 2014; DOI: 10.1158/1940-6207.CAPR-14-0233 Cancer Prevention Research Article Research Crucial Role of c-Jun Phosphorylation at Ser63/73 Mediated by PHLPP Protein Degradation in the Cheliensisin A Inhibition of Cell Transformation Junlan Zhu1,2, Jingjie Zhang1, Haishan Huang1,2, Jingxia Li1, Yonghui Yu1, Honglei Jin1,2, Yang Li1,2, Xu Deng3, Jimin Gao2, Qinshi Zhao3, and Chuanshu Huang1 Abstract Cheliensisin A (Chel A), as a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been demonstrated to have an inhibition of EGF-induced Cl41 cell transformation via stabilizing p53 protein in a Chk1-dependent manner, suggesting its chemopreventive activity in our previous studies. However, its underlying molecular mechanisms have not been fully characterized yet. In the current study, we found that Chel A treatment could increase c-Jun protein phosphorylation and activation, whereas the inhibition of c-Jun phosphorylation, by ectopic expression of a dominant-negative mutant of c-Jun, TAM67, reversed the Chel A inhibition of EGF-induced cell transformation and impaired Chel A induction of p53 protein and apoptosis. Moreover, our results indicated that Chel A treatment led to a PHLPP downregulation by promoting PHLPP protein degradation. We also found that PHLPP could interact with and bind to c-Jun protein, whereas ectopic PHLPP expression blocked c-Jun activation, p53 protein and apoptotic induction by Chel A, and further reversed the Chel A inhibition of EGF-induced cell transformation. With the findings, we have demonstrated that Chel A treatment promotes a PHLPP protein degradation, which can bind to c-Jun and mediates c-Jun phosphorylation, and further leading to p53 protein induction, apoptotic responses, subsequently resulting in cell transformation inhibition and chemopreventive activity of Chel A. -
The Rich World of P53 DNA Binding Targets: the Role of DNA Structure
International Journal of Molecular Sciences Review The Rich World of p53 DNA Binding Targets: The Role of DNA Structure Václav Brázda * and Miroslav Fojta Institute of Biophysics of the Czech Academy of Sciences, Královopolská 135, 612 65 Brno, Czech Republic; [email protected] * Correspondence: [email protected]; Tel.: +420-541-517-231 Received: 11 October 2019; Accepted: 8 November 2019; Published: 9 November 2019 Abstract: The tumor suppressor functions of p53 and its roles in regulating the cell cycle, apoptosis, senescence, and metabolism are accomplished mainly by its interactions with DNA. p53 works as a transcription factor for a significant number of genes. Most p53 target genes contain so-called p53 response elements in their promoters, consisting of 20 bp long canonical consensus sequences. Compared to other transcription factors, which usually bind to one concrete and clearly defined DNA target, the p53 consensus sequence is not strict, but contains two repeats of a 50RRRCWWGYYY30 sequence; therefore it varies remarkably among target genes. Moreover, p53 binds also to DNA fragments that at least partially and often completely lack this consensus sequence. p53 also binds with high affinity to a variety of non-B DNA structures including Holliday junctions, cruciform structures, quadruplex DNA, triplex DNA, DNA loops, bulged DNA, and hemicatenane DNA. In this review, we summarize information of the interactions of p53 with various DNA targets and discuss the functional consequences of the rich world of p53 DNA binding targets for its complex regulatory functions. Keywords: p53; protein-DNA interactions; consensus sequence; cruciform; local DNA structures 1. Introduction p53 is the most often mutated tumor suppressor in humans and is studied intensively from different points of view due to its crucial role in malignant transformation [1–3]. -
A Thyroid Hormone Receptor Coactivator Negatively Regulated by the Retinoblastoma Protein
Proc. Natl. Acad. Sci. USA Vol. 94, pp. 9040–9045, August 1997 Biochemistry A thyroid hormone receptor coactivator negatively regulated by the retinoblastoma protein KAI-HSUAN CHANG*†,YUMAY CHEN*†,TUNG-TI CHEN*†,WEN-HAI CHOU*†,PHANG-LANG CHEN*, YEN-YING MA‡,TERESA L. YANG-FENG‡,XIAOHUA LENG§,MING-JER TSAI§,BERT W. O’MALLEY§, AND WEN-HWA LEE*¶ *Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, TX 78245; ‡Department of Genetics, Obstetrics, and Gynecology, Yale University School of Medicine, New Haven, CT 06510; and §Department of Cell Biology, Baylor College of Medicine, Houston, TX 77030 Contributed by Bert W. O’Malley, June 9, 1997 ABSTRACT The retinoblastoma protein (Rb) plays a E2F-1, a transcription factor important for the expression of critical role in cell proliferation, differentiation, and devel- several genes involved in cell cycle progression from G1 to S opment. To decipher the mechanism of Rb function at the (18). Rb inhibits E2F-1 activity by blocking its transactivation molecular level, we have systematically characterized a num- region (19–21). In contrast, Rb has been shown to have the ber of Rb-interacting proteins, among which is the clone C5 ability to increase the transactivating activity of the members described here, which encodes a protein of 1,978 amino acids of the CCAATyenhancer binding protein (CyEBP) family, and with an estimated molecular mass of 230 kDa. The corre- to be required for CyEBPs-dependent adipocyte and mono- sponding gene was assigned to chromosome 14q31, the same cytes differentiation (16–17).