DOCSLIB.ORG

Relationship Between E1A Binding to Cellular Proteins, C-Myc Activation and S-Phase Induction

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Relationship Between E1A Binding to Cellular Proteins, C-Myc Activation and S-Phase Induction Oncogene (2007) 26, 781–787 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc SHORT COMMUNICATION Relationship between E1A binding to cellular proteins, c-myc activation and S-phase induction S Baluchamy1,3,4, N Sankar1,3, A Navaraj1,5, E Moran2 and B Thimmapaya1 1Department of Microbiology–Immunology Feinberg School of Medicine, Northwestern University, Chicago, IL, USA and 2Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA, USA We recently showed that p300/CREB-binding protein Cell transformation by the adenoviral E1A oncoprotein (CBP) plays an important role in maintaining cells in G0/ is dependent on its binding to and inactivating several G1 phase by keeping c-myc in a repressed state. host proteins including p400, p300, pRb, and the two Consistent with this, adenovirus E1A oncoprotein induces Rb family proteins p130 and p107, PCAF, TRRAP and c-myc in a p300-dependent manner, and the c-myc GCN5 (reviewed in Moran, 1993; Barbeau et al., 1994; induction is linked to S-phase induction. The induction Frisch and Mymryk, 2002); for an extensive list of of S phase by E1A is dependent on its binding to and references on this topic please refer to the web site inactivating several host proteins including p300/CBP. To http://www.geocities.com/jmymryk.geo/. These host determine whether there is a correlation between the host proteins are found in distinct chromatin remodeling proteins binding to the N-terminal region of E1A, complexes that modulate gene expression either by activation of c-myc and induction of S phase, we assayed activating or repressing transcription. In most cases, the c-myc and S-phase induction in quiescent human cells specific transcriptional targets of these complexes in the by infecting them with Ad N-terminal E1A mutants with context of cell cycle and the mechanism by which E1A mutations that specifically affect binding to different interferes in their function are not known. pRb, p130 chromatin-associated proteins including pRb, p300, p400 and p107proteins in association with histone deacety- and p300/CBP-associated factor (PCAF). We show that lases repress E2F1 function that is critical for the the mutants that failed to bind to p300 or pRb were induction of S phase (Harbour, 2001). p400 is a severely defective for c-myc and S-phase induction. The component of the human TIP60/NuA4 complex con- induction of c-myc and S phase was only moderately taining histone acetyl transferase (HAT) activity that affected when E1A failed to bind to p400. Furthermore, modulates both transcriptional repression and activa- analysis of the E1A mutants that fail to bind to p300, and tion (Fuchs et al., 2001; Doyon et al., 2004). p300 and both p300 and PCAF suggests that PCAF may also play a CREB-binding protein (CBP) are two large highly role in c-myc repression, and that the two chromatin- homologous nuclear phosphoproteins containing associated proteins may repress c-myc independently. In HAT activity that function as transcriptional coactivators summary, these results suggest that c-myc deregulation by and link chromatin remodeling with transcription E1A through its interaction with these chromatin-asso- (Goodman and Smolik, 2000). TRRAP is found in ciated proteins is an important step in the E1A-mediated three distinct human HAT complexes including the cell cycle deregulation and possibly in cell transformation. TIP60 HAT complex and two other complexes that are Oncogene (2007) 26, 781–787. doi:10.1038/sj.onc.1209825; similar to yeast SAGA (Spt-Ada-Gcn5-acetyl transferase published online 24 July 2006 complex) containing either GCN5 or PCAF (reviewed in Sterner and Berger, 2000). Keywords: E1A; p300; c-myc repression; cell cycle Until recently, the significance of E1A binding to p300 in the E1A-mediated cell cycle deregulation and cell transformation was not known. We recently showed that in quiescent human cells, p300/CBP plays an important role in keeping c-myc in a repressed state. Depletion and induction of p300/CBP in serum-starved cells led to induction and repression, respectively, of Correspondence: Dr B Thimmapaya, Department of Microbiology— c-myc and DNA synthesis (Kolli et al., 2001; Baluchamy Immunology, Feinberg School of Medicine, Northwestern University, et al., 2003; Rajabi et al., 2005). Consistent with this, we 303 East Chicago Avenue, Olson 8452, Chicago, IL 60611, USA. E-mail: [email protected] showed that in quiescent cells, E1A induced c-myc in a 3These two authors contributed equally to this work. p300-dependent manner indicating that E1A interferes 4Current address: Department of Genetics and Biochemistry, Uni- with p300/CBP repression of c-myc (Kolli et al., 2001). versity of Illinois at Chicago, Chicago, IL, USA. To determine whether or not there is a correlation 5Current address: Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. between E1A binding to host proteins, and induction of Received 28 September 2005; revised 9 June 2006; accepted 11 June 2006; c-myc and S phase, we have studied a series of previously published online 24 July 2006 characterized E1A mutants for their capacity to induce c-myc activation by adenovirus E1A S Baluchamy et al 782 c-myc and to enter S phase. Our results show that the either of the mutations alone; Wang et al., 1995), it was E1A mutants that do not bind to p300 or Rb do not as defective as 928 in inducing c-myc, suggesting that the induce c-myc and S phase, whereas a mutant that does effects of RG2 mutation were further reduced by 928 not bind to p400 induces both c-myc and cell cycle mutation suggesting that WT E1A may recruit both efficiently. In addition, our studies suggest that E1A p300 and Rb simultaneously as suggested earlier (Wang binding to PCAF may also independently contribute to et al., 1995). In contrast, mutant dl2–36 (aa 2–36 c-myc induction. deleted) that binds to neither p300 nor p400 showed a Figure 1 shows a schematic of the E1A mutants dramatic decrease in c-myc RNA levels that was analysed in this study that were characterized exten- comparable to that of control samples. All of the E1A sively by several laboratories with respect to their mutants used in these studies expressed their respective capacity to bind to different host proteins in vivo, proteins, at reasonable levels as shown by a Western induce DNA synthesis and transform rodent cells in blot in Figure 2d. culture in the presence of activated ras (references cited Comparison of the c-myc induction and the protein above; also see Egan et al., 1988; Fuchs et al., 2001; binding properties of the mutant dl26–35, RG2 and dl2– Lang and Hearing, 2003). To determine the capacity of 36 suggested that host proteins other than Rb and p300 these mutants to induce c-myc and DNA synthesis in might also repress c-myc. For example, mutant dl26–35 human cells, we used MCF10A cells (an immortalized induces c-myc to near-normal levels (Figure 2a), and it non-transformed human breast epithelial cell line; Soule does not bind to p400, and also TRRAP and GCN5; its et al., 1990) that can be growth arrested by serum p300 and PCAF binding capacity is not affected (Lang starvation and show normal serum-stimulated induction and Hearing, 2003). RG2, which retains about 40% of of c-myc and cell cycle (Kolli et al., 2001). its Myc-inducing capacity, binds to p400 at normal To determine the levels of c-myc induced by the E1A levels, whereas it does not bind to p300 (TRRAP and mutants, serum-starved MCF10A cells were infected GCN5 binding is not tested). In contrast, dl2–36 that is with Ad mutants described above for 12 h, and the RNA inactive in inducing c-myc does not bind to both p400 samples were analysed using a quantitative real-time and p300. As dl2–36 also contains dl26–35 deletion, it is PCR assay as described in the legend to Figure 2. An Ad not expected to bind to TRRAP and GCN5 as well. vector expressing beta-galactosidase (Adb-gal) was used Thus, it seemed possible that the total loss of c-myc as a control, and the fold-increase in c-myc induction by induction by dl2–36 may be owing to its inability to bind the E1A mutants was compared to that of Adb-gal- to p300 and another protein such as PCAF as PCAF infected cells. As shown in Figure 2a, there was about and p300 binding regions on E1A overlap (Lang and sixfold induction of c-myc in WT-infected cells. In Hearing, 2003). To test this possibility, MCF10A cells contrast, in cells infected with RG2 (arginine-2 changed were infected for 16 h with WT, RG2 and dl2–36 along to glycine) that does not bind to p300, c-myc induction with an Ad vector expressing FLAG epitope-tagged was only about 2.5-fold. Similarly, the mutant 928 PCAF from the cytomegalovirus (CMV) promoter (cysteine-128 changed to glycine) that does not bind to (AdPCAF). The cell lysates were immunoprecipitated Rb also was severely defective for c-myc induction with with an anti-FLAG antibody followed by Western a 1.7-fold increase of c-myc RNA levels, suggesting a immunoblotting with an anti-E1A antibody. As shown role for pRb in c-myc repression. E1A mutant that does in Figure 2e, both WT and RG2 E1A proteins bound to not bind to p400 (dl1102, deletion of aa 26–35; referred PCAF at comparable levels. Reverse experiment (Im- to here as dl26–35) induced near-normal levels of c-myc munoprecipitation with anti-E1A and Western with RNA (5.5-fold).
Load more

Recommended publications
  • Functional Roles of Bromodomain Proteins in Cancer
    cancers Review Functional Roles of Bromodomain Proteins in Cancer Samuel P. Boyson 1,2, Cong Gao 3, Kathleen Quinn 2,3, Joseph Boyd 3, Hana Paculova 3 , Seth Frietze 3,4,* and Karen C. Glass 1,2,4,* 1 Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA; [email protected] 2 Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; [email protected] 3 Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; [email protected] (C.G.); [email protected] (J.B.); [email protected] (H.P.) 4 University of Vermont Cancer Center, Burlington, VT 05405, USA * Correspondence: [email protected] (S.F.); [email protected] (K.C.G.) Simple Summary: This review provides an in depth analysis of the role of bromodomain-containing proteins in cancer development. As readers of acetylated lysine on nucleosomal histones, bromod- omain proteins are poised to activate gene expression, and often promote cancer progression. We examined changes in gene expression patterns that are observed in bromodomain-containing proteins and associated with specific cancer types. We also mapped the protein–protein interaction network for the human bromodomain-containing proteins, discuss the cellular roles of these epigenetic regu- lators as part of nine different functional groups, and identify bromodomain-specific mechanisms in cancer development. Lastly, we summarize emerging strategies to target bromodomain proteins in cancer therapy, including those that may be essential for overcoming resistance. Overall, this review provides a timely discussion of the different mechanisms of bromodomain-containing pro- Citation: Boyson, S.P.; Gao, C.; teins in cancer, and an updated assessment of their utility as a therapeutic target for a variety of Quinn, K.; Boyd, J.; Paculova, H.; cancer subtypes.
    [Show full text]
  • Estrogen-Related Receptor Alpha: an Under-Appreciated Potential Target for the Treatment of Metabolic Diseases
    International Journal of Molecular Sciences Review Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases Madhulika Tripathi, Paul Michael Yen and Brijesh Kumar Singh * Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore 169857, Singapore; [email protected] (M.T.); [email protected] (P.M.Y.) * Correspondence: [email protected] Received: 7 February 2020; Accepted: 24 February 2020; Published: 28 February 2020 Abstract: The estrogen-related receptor alpha (ESRRA) is an orphan nuclear receptor (NR) that significantly influences cellular metabolism. ESRRA is predominantly expressed in metabolically-active tissues and regulates the transcription of metabolic genes, including those involved in mitochondrial turnover and autophagy. Although ESRRA activity is well-characterized in several types of cancer, recent reports suggest that it also has an important role in metabolic diseases. This minireview focuses on the regulation of cellular metabolism and function by ESRRA and its potential as a target for the treatment of metabolic disorders. Keywords: estrogen-related receptor alpha; mitophagy; mitochondrial turnover; metabolic diseases; non-alcoholic fatty liver disease (NAFLD); adipogenesis; adaptive thermogenesis 1. Introduction When the estrogen-related receptor alpha (ESRRA) was first cloned, it was found to be a nuclear receptor (NR) that had DNA sequence homology to the estrogen receptor alpha (ESR1) [1]. There are several examples of estrogen-related receptor (ESRR) and estrogen-signaling cross-talk via mutual transcriptional regulation or reciprocal binding to each other’s response elements of common target genes in a context-specific manner [2,3].
    [Show full text]
  • Regulation of Mouse Embryonic and Extraembryonic Morphogenesis by Zfp568 and Trim28
    REGULATION OF MOUSE EMBRYONIC AND EXTRAEMBRYONIC MORPHOGENESIS BY ZFP568 AND TRIM28 A Dissertation Presented to the Faculty of the Graduate School of Cornell University In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy by Maho Shibata January 2011 © 2011 Maho Shibata REGULATION OF MOUSE EMBRYONIC AND EXTRAEMBRYONIC MORPHOGENESIS BY ZFP568 AND TRIM28 Maho Shibata, Ph. D. Cornell University 2011 In mammals, extraembryonic tissues are critical for sustaining embryonic life inside the uterus, providing nourishment and secreting factors to maintain pregnancy. However, our understanding of the genes controlling the morphogenesis of these tissues is still limited. chato, an ENU allele disrupting the mouse Kruppel-associated box (KRAB) zinc finger protein ZFP568, causes unique defects in the morphogenesis of extraembryonic tissues including yolk sac ruffling, incomplete formation of a yolk sac vascular plexus, and failure to form a normal placenta. Most chato embryos have an expanded chorionic ectoderm that, in extreme cases, prevents the closure of the ectoplacental cavity. Interestingly, I found that the severity of yolk sac defects in chato embryos correlated with trophoblast malformations, suggesting that all extraembryonic defects in chato mutants have a common developmental origin. To address the requirements of Zfp568 in different extraembryonic lineages, I analyzed chimeric embryos generated by both tetraploid complementation assays and by the use of a reversible allele of Zfp568 in combination with Cre lines. My results indicate that ZFP568 is required in the extraembryonic mesoderm to regulate the morphogenesis of the yolk sac and placenta, and support a previously undescribed role of the extraembryonic mesoderm in the morphogenesis of extraembryonic tissues.
    [Show full text]
  • Post-Translational Control of Retinoblastoma Protein Phosphorylation
    Western University Scholarship@Western Electronic Thesis and Dissertation Repository 9-25-2014 12:00 AM Post-Translational Control of Retinoblastoma Protein Phosphorylation Paul M. Stafford The University of Western Ontario Supervisor Dr. Fred Dick The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Master of Science © Paul M. Stafford 2014 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Biochemistry Commons, and the Molecular Biology Commons Recommended Citation Stafford, Paul M., "Post-Translational Control of Retinoblastoma Protein Phosphorylation" (2014). Electronic Thesis and Dissertation Repository. 2449. https://ir.lib.uwo.ca/etd/2449 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. POST-TRANSLATIONAL CONTROL OF RETINOBLASTOMA PROTEIN PHOSPHORYLATION (Thesis format: Integrated Article) by Paul Stafford Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science The School of Graduate and Postdoctoral Studies The University of Western Ontario London, Ontario, Canada © Paul Stafford 2015 i Abstract The retinoblastoma tumor suppressor protein (pRB) functions through multiple mechanisms to serve as a tumor suppressor. pRB has been well characterized to be inactivated through phosphorylation by CDKs. pRB dephosphorylation and activation is a much less characterized aspect of pRB function. In this thesis, I detail work to study the post translational control of pRB phosphorylation.
    [Show full text]
  • Transcription Factor SPZ1 Promotes TWIST-Mediated Epithelial–Mesenchymal Transition and Oncogenesis in Human Liver Cancer
    OPEN Oncogene (2017) 36, 4405–4414 www.nature.com/onc ORIGINAL ARTICLE Transcription factor SPZ1 promotes TWIST-mediated epithelial–mesenchymal transition and oncogenesis in human liver cancer L-T Wang1, S-S Chiou2,3, C-Y Chai4, E Hsi5, C-M Chiang6, S-K Huang7, S-N Wang8,9, KK Yokoyama1,10,11,12,13,14 and S-H Hsu1,12 The epithelial–mesenchymal transition (EMT) is an important process in the progression of cancer. However, its occurrence and mechanism of regulation are not fully understood. We propose a regulatory pathway in which spermatogenic leucine zipper 1 (SPZ1) promotes EMT through its transactivating ability in increasing TWIST1 expression. We compared the expression of SPZ1 and TWIST1 in specimens of hepatocarcinoma cells (HCCs) and non-HCCs. Expression of SPZ1 exhibited a tumor-specific expression pattern and a high correlation with patients’ survival time, tumor size, tumor number and progression stage. Moreover, forced expression and knockdown of SPZ1 in hepatoma cells showed that SPZ1 was able to regulate the cellular proliferation, invasion, and tumorigenic activity in a TWIST1-dependent manner in vitro and in vivo. These data demonstrate that SPZ1, a newly dscribed molecule, transactivates TWIST1 promoters, and that this SPZ1-TWIST axis mediates EMT signaling and exerts significant regulatory effects on tumor oncogenesis. Oncogene (2017) 36, 4405–4414; doi:10.1038/onc.2017.69; published online 3 April 2017 INTRODUCTION by phosphorylation, which results in SPZ1 translocation into the Despite the identification of potential oncogenic drivers and their nucleus and activation of downstream gene expression such as 16 roles as master regulators of cancer initiation, the underlying the proliferating cell nuclear antigen.
    [Show full text]
  • The Histone Acetylase PCAF Is a Nuclear Receptor Coactivator
    Downloaded from genesdev.cshlp.org on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press The histone acetylase PCAF is a nuclear receptor coactivator Jorge C.G. Blanco,1,4 Saverio Minucci,1 Jianming Lu,1 Xiang-Jiao Yang,1 Kristen K. Walker,3 Hongwu Chen,3 Ronald M. Evans,2,3 Yoshihiro Nakatani,1 and Keiko Ozato1,5 1Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland 20892-2753 USA; 2Howard Hughes Medical Institute; 3The Salk Institute for Biological Studies, La Jolla, California 92037 USA Whereas the histone acetylase PCAF has been suggested to be part of a coactivator complex mediating transcriptional activation by the nuclear hormone receptors, the physical and functional interactions between nuclear receptors and PCAF have remained unclear. Our efforts to clarify these relationships have revealed two novel properties of nuclear receptors. First, we demonstrate that the RXR/RAR heterodimer directly recruits PCAF from mammalian cell extracts in a ligand-dependent manner and that increased expression of PCAF leads to enhanced retinoid-responsive transcription. Second, we demonstrate that, in vitro, PCAF directly associates with the DNA-binding domain of nuclear receptors, independently of p300/CBP binding, therefore defining a novel cofactor interaction surface. Furthermore, our results show that dissociation of corepressors enables ligand-dependent PCAF binding to the receptors. This observation illuminates how a ligand-dependent receptor function can be propagated to regions outside the ligand-binding domain itself. On the basis of these observations, we suggest that PCAF may play a more central role in nuclear receptor function than previously anticipated.
    [Show full text]
  • Delineation of Key Regulatory Elements Identifies Points Of
    DELINEATION OF KEY REGULATORY ELEMENTS IDENTIFIES POINTS OF VULNERABILITY IN THE MITOGEN-ACTIVATED SIGNALING NETWORK SUPPLEMENTARY MATERIALS List of contents Supplementary Figures with legends 1. Figure S1: Distribution of primary siRNA screen data, and standardization of assay procedure. 2. Figure S2: Scatter plot of screen data. 3. Figure S3: Functional relevance of the identified targets and Calculation of residence time from PDT and cell cycle distribution. 4. Figure S4: FACS profiles for ABL1 and AKT1. Table for data in Figure 5B. 5. Figure S5: Venn diagram showing the results of the comparative analysis of other screen results 6. Figure S6: Dose response profiles for the AKT1 + ABL1 inhibitor combination for CH1, list of the 14 cell lines and their description, effect of ABL1+AKT1 inhibitor combination on increase in apoptotic cells and G1 arrest in 14 cell lines, effects of CHEK1 inhibitor on combination C1,C2 on 4 cell lines. Supplementary Tables 1. Table S1: siRNA screen results for targeted kinases and phosphatases. 2. Table S2: Gene expression status of the validated hits. 3. Table S3: Role played by identified RNAi hits in regulation of cell cycle, the effect on PDTs along with phase-specific RTs. 4. Table S4: List of molecules classified as cell cycle targets. 5. Table S5: High confidence network used for graph theory analysis. 6. Table S6: Occurrences of nodes in shortest path networks. 7. Table S7: Network file used as SNAVI background. 8. Table S8: Classification of nodes present in modules according to specificity. Legends for tables Supplementary Experimental Procedures References Figure S1 A 450 400 G1 S 350 G2 300 250 200 150 100 50 Distribution of molecules Distribution 0 -6-4-20246 Z-score 350 200 400 G1 S 300 G2 150 300 250 200 100 200 150 100 50 100 Distribution of molecules 50 0 0 0 -4 -2 0 2 4 -4-20246 -4-20246 Z-score B PLK1 GAPDH PLCg BTK PLCg CDC2A PLCg CHEK1 PLCg MET Distribution profiles of complete primary screen and western blots showing knockdown efficiency.
    [Show full text]
  • Acetyltransferase Machinery Conserved in P300/CBP-Family Proteins
    Oncogene (2002) 21, 2253 ± 2260 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc SHORT REPORT Acetyltransferase machinery conserved in p300/CBP-family proteins L Wuchao Yuan1 and Antonio Giordano*,2 1Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, MA 02118, USA; 2Department of Pathology, Anatomy and Cell Biology, Jeerson Medical College, Philadelphia, Pennsylvania, PA 19107, USA CREB-binding protein (CBP) and p300 are highly supports this proposal. Later, this protein family was conserved and functionally related transcription coacti- expanded after the discovery of Drosophila CBP (dCBP), vators and histone/protein acetyltransferases. They are which was also able to bind to E1A and coactivate tumor suppressors, participate in a wide variety of CREB-dependent transactivation (Akimaru et al., physiological events, and serve as integrators among 1997a). Recently, p300/CBP-like proteins of the plant dierent signal transduction pathways. In this study, 11 Arabidopsis thaliana have been reported (Bordoli et al., distinct proteins that have a high degree of homology 2001), suggesting that they are possible members of the with the amino acid sequence of p300 have been p300/CBP family. It is interesting to know how large the identi®ed in current protein databases. All of these 11 p300/CBP protein family could be and how this family of proteins belong to either animal or plant multicellular proteins is conserved evolutionarily. organisms (higher eucaryotes). Conservation of p300/ Taking advantage of recent progress in genomic CBP domains among these proteins was examined sequencing of dierent organisms, we performed a blast further by sequence alignment and pattern search.
    [Show full text]
  • Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling Through TRIM24
    Author Manuscript Published OnlineFirst on October 11, 2017; DOI: 10.1158/0008-5472.CAN-17-1388 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Histone acetyltransferase KAT6A upregulates PI3K/AKT signaling through TRIM24 binding Deguan Lv1,2*, Feng Jia3*, Yanli Hou4*, Youzhou Sang2, Angel A. Alvarez5, Weiwei Zhang2, Wei-Qiang Gao2, Bo Hu5, Shi-Yuan Cheng2,5, Jianwei Ge3, Yanxin Li6 and Haizhong Feng2 1State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China 2Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital 3Department of Neurosurgery, Ren Ji Hospital 4Department of Radiotherapy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China 5Department of Neurology, Northwestern Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA 6Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Pediatric Translational Medicine Institute, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China *These authors contributed equally to this work. Running title: KAT6A promotes glioma tumorigenesis Keywords: KAT6A; glioma; PIK3CA; Akt; TRIM24 Correspondence: Haizhong Feng, State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Phone: 1 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 11, 2017; DOI: 10.1158/0008-5472.CAN-17-1388 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Structure and Function Relationships in the Pgc-1 Family of Transcriptional Coactivators
    From Department of Physiology and Pharmacology Karolinska Institutet, Stockholm, Sweden STRUCTURE AND FUNCTION RELATIONSHIPS IN THE PGC-1 FAMILY OF TRANSCRIPTIONAL COACTIVATORS Manizheh Izadi Stockholm 2018 All previously published papers were reproduced with permission from the publisher. Published by Karolinska Institutet. Cover illustration by Mattias Karlen Printed by Eprint AB 2018 © Manizheh Izadi, 2018 ISBN 978-91-7831-130-9 Structure and function relationships in the PGC-1 family of transcriptional coactivators THESIS FOR DOCTORAL DEGREE (Ph.D.) By Manizheh Izadi Principal Supervisor: Opponent: Jorge Lira Ruas Professor Christoph Handschin Karolinska Institutet University of Basel Department of Physiology and Pharmacology Biozentrum Division of Molecular and Cellular exercise physiology Examination Board: Associate Professor Jurga Laurencikiene Co-supervisor: Karolinska Institutet Teresa Pereira Department of Medicine Karolinska Institutet Division of Endocrinology and Diabetes Department of Molecular Medicine and Surgery Associate Professor Anita Öst Linköping University Department of Clinical and Experimental Medicine Division of Neurobiology Associate Professor Helena Berglund Karolinska Institutet Department of Medical Biochemistry and Biophysics Division of Protein Science Facility To my loves, My parents, Maman and Baba For everything ABSTRACT PGC-1 coactivators are central regulators of several cellular processes, most notably the coupling between energy demands and supply. PGCs activate distinct biological processes in a tissue-specific manner. These include mitochondrial biogenesis, oxidative phosphorylation, oxygen transport, gluconeogenesis, angiogenesis, and muscle fiber-type specification. The family consists of three members: PGC-1α, PGC-1β, and PRC, among which the most studied is PGC-1α. Transcription of a single PGC-1α gene produces different isoforms (e.g. PGC-1α1 to α4) with different biological functions.
    [Show full text]
  • Transcriptional and Epigenetic Control of Brown and Beige Adipose Cell Fate and Function
    REVIEWS Transcriptional and epigenetic control of brown and beige adipose cell fate and function Takeshi Inagaki1,2, Juro Sakai1,2 and Shingo Kajimura3 Abstract | White adipocytes store excess energy in the form of triglycerides, whereas brown and beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes. Interscapular BAT Adipose tissue has a central role in whole-body energy subjects who had previously lacked detectable BAT Brown adipose tissue (BAT) is a homeostasis. White adipose tissue (WAT) is the major depots before cold exposure, presumably owing to the specialized organ that adipose organ in mammals. It represents 10% or more emergence of new thermogenic adipocytes. This, then, produces heat. BAT is localized of the body weight of healthy adult humans and is leads to an increase in non-shivering thermogenesis in the interscapular and 6–9 perirenal regions of rodents specialized for the storage of excess energy. Humans and/or an improvement in insulin sensitivity . These and infants.
    [Show full text]
  • Histone Acetyltransferase PCAF Is Required for Hedgehog– Gli-Dependent Transcription and Cancer Cell Proliferation
    Published OnlineFirst August 13, 2013; DOI: 10.1158/0008-5472.CAN-12-4660 Cancer Tumor and Stem Cell Biology Research Histone Acetyltransferase PCAF Is Required for Hedgehog– Gli-Dependent Transcription and Cancer Cell Proliferation Martina Malatesta1,2, Cornelia Steinhauer1,2, Faizaan Mohammad1,2, Deo P. Pandey1,2, Massimo Squatrito4, and Kristian Helin1,2,3 Abstract The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh–Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of aberrant Hh–Gli signaling has, thus, emerged as an attractive approach for anticancer therapy; however, the mechanisms that mediate Hh–Gli signaling in vertebrates remain poorly understood. Here, we show that the histone acetyltransferase PCAF/KAT2B is an important factor of the Hh pathway. Specifically, we show that PCAF depletion impairs Hh activity and reduces expression of Hh target genes. Consequently, PCAF downregulation in medulloblastoma and glioblastoma cells leads to decreased proliferation and increased apoptosis. In addition, we found that PCAF interacts with GLI1, the downstream effector in the Hh–Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Finally, we observed that PCAF silencing reduces the tumor-forming potential of neural stem cells in vivo. In summary, our study identified the acetyltransferase PCAF as a positive cofactor of the Hh–Gli signaling pathway, leading us to propose PCAF as a candidate therapeutic target for the treatment of patients with medulloblastoma and glioblastoma.
    [Show full text]