DOCSLIB.ORG

The Molecular Balancing Act of P16 in Cancer and Aging

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Molecular Balancing Act of P16 in Cancer and Aging Published OnlineFirst October 17, 2013; DOI: 10.1158/1541-7786.MCR-13-0350 Molecular Cancer Review Research The Molecular Balancing Act of p16INK4a in Cancer and Aging Kyle M. LaPak1 and Christin E. Burd1,2 Abstract p16INK4a, located on chromosome 9p21.3, is lost among a cluster of neighboring tumor suppressor genes. Although it is classically known for its capacity to inhibit cyclin-dependent kinase (CDK) activity, p16INK4a is not just a one-trick pony. Long-term p16INK4a expression pushes cells to enter senescence, an irreversible cell-cycle arrest that precludes the growth of would-be cancer cells but also contributes to cellular aging. Importantly, loss of p16INK4a is one of the most frequent events in human tumors and allows precancerous lesions to bypass senescence. Therefore, precise regulation of p16INK4a is essential to tissue homeostasis, maintaining a coordinated balance between tumor suppression and aging. This review outlines the molecular pathways critical for proper p16INK4a regulation and emphasizes the indispensable functions of p16INK4a in cancer, aging, and human physiology that make this gene special. Mol Cancer Res; 12(2); 1–17. Ó2013 AACR. Introduction frames (ORF) to yield two distinct proteins: p16INK4a and ARF ARF Every day, we depend on our cells to make the right ARF (p14 in humans and p19 in mice). In addition to — CDKN2A,theINK4/ARF locus encodes a third tumor decision to divide or not to divide. Proliferation is essential INK4b for tissue homeostasis, but, when deregulated, it can both suppressor protein, p15 ,justupstreamoftheARF promoter (3). Discovered through homology-based cDNA promote cancer and lead to aging. For this reason, the INK4b INK4a decision to replicate is tightly controlled by a complex library screens, p15 functions analogously to p16 , – directly blocking the interaction of CDK4/6 with D-type network of cell-cycle regulatory proteins. In the early INK4b INK4a 1990s, it was clear that the catalytic activity of cyclin- cyclins (2, 3). In contrast to p15 and p16 ,which dependent kinases (CDKs) was required to drive cellular function to inhibit RB phosphorylation, ARF expression division. Less obvious were the signals that regulate CDK stabilizes and thereby activates another tumor suppressor, activity and how these became altered in neoplastic disease. p53 (5, 6). Like the INK family of inhibitors, p53 functions to In an attempt to address this very question, Beach and block inappropriate proliferation and cellular transformation. colleagues made the observation that CDK4 bound a dis- Through a poorly understood mechanism, likely dependent tinct, 16-kDa protein in cells transduced with a viral onco- upon cell type and transcriptional output, p53 activation can gene (1). Biochemical characterization of this protein, later trigger either apoptosis or cell-cycle arrest (7). A fourth INK4/ named p16INK4a, placed it amongst the INK4-class of cell- ARF transcript, ANRIL (Antisense Noncoding RNA in the cycle inhibitors, which bind directly to CDK4 and CDK6, INK4/ARF Locus), was recently discovered in a familial blocking phosphorylation of the retinoblastoma tumor sup- melanoma kindred with neural system tumors (8). The ANRIL transcript runs antisense to p15INK4b and encodes a pressor (RB) and subsequent traversal of the G1/S cell-cycle checkpoint (Fig. 1A; refs 2, 3). In the presence of various long, noncoding RNA elevated in prostate cancer and leu- stressors (e.g., oncogenic signaling, DNA damage), p16INK4a kemia (9, 10). ANRIL is proposed to function as an epigenetic expression blocks inappropriate cellular division, and pro- regulator of INK4/ARF gene transcription, targeting histone- longed induction of p16INK4a leads to an irreversible cell- modifying enzymes to the locus (see the Discussion section). cycle arrest termed "cellular senescence". In summary, the INK4/ARF locus is a relatively small (110 The gene encoding p16INK4a, CDKN2A,lieswithinthe kb), but complex locus, essential to the proper maintenance of INK4/ARF tumor suppressor locus on human chromosome cell-cycle control and tumor suppression. In this review, we 9p21.3 (Fig. 1B). CDKN2A encodes two transcripts with focus on the founding member of the INK4/ARF locus, p16INK4a, and discuss what is known and unknown about alternative transcriptional start sites (4). Both transcripts share INK4a exons 2 and 3, but are translated in different open reading p16 regulation in cancer and aging. CDK4/6-independent roles of p16INK4a INK4a Authors' Affiliations: Departments of 1Molecular Genetics and 2Molecular Several lines of evidence suggest that p16 may and Cellular Biochemistry, The Ohio State University, Columbus, Ohio function both through CDK4/6-dependent and -indepen- – Corresponding Author: Christin E. Burd, Biomedical Research Tower, Rm dent mechanisms to regulate the cell cycle. CYCLIN D 586, The Ohio State University, 460 W. 12th Avenue, Columbus, OH 43210. CDK4/6 complexes are stabilized by interactions with the Phone: 614-688-7569; Fax: 614-292-6356; E-mail: [email protected] CDK2 inhibitors, p21CIP1, p27KIP1, and p57KIP2, and serve doi: 10.1158/1541-7786.MCR-13-0350 to titrate these proteins away from CDK2 (11–14). Subse- INK4a INK4b Ó2013 American Association for Cancer Research. quent expression of p16 or p15 causes these www.aacrjournals.org OF1 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst October 17, 2013; DOI: 10.1158/1541-7786.MCR-13-0350 LaPak and Burd Figure 1. Function, structure, and polymorphisms of the INK4/ARF locus. A, p15INK4b and p16INK4a both function in the RB tumor suppressor pathway through inhibition of CDK4/6 activity. Expression of p14ARF inhibits the E3 ubiquitin ligase activity of MDM2, leading to stabilization of p53. The p53 and RB pathways play integral roles in blocking inappropriate cellular proliferation. B, packed into 35 kb of chromosome 9p21.3 are three well-characterized tumor ARF INK4b INK4a suppressor genes: p14 , p15 , and p16 . GWAS have implicated 9p21.3 SNPs in cancer, heart disease, glaucoma, type 2 diabetes, autism, and endometriosis. The majority of the SNPs lie outside of the coding regions in a recently discovered long, noncoding RNA, ANRIL. Of the identified SNPs, those that have been shown to correlate with CDKN2A expression in at least one study are filled with gray. Other SNPs that have not been correlated with CDKN2A expression in validation studies, or have yet to be examined are filled with black or white, respectively. complexes to disassociate, releasing sequestered CDK2 inhi- or p19INK4d) develop normally, and are born at expected bitors (15). This process, known as "CDK inhibitor re- mendelian ratios (23–25). In contrast, p18INK4c KOs are shuffling", has been documented in a growing list of cell characterized by organomegaly; yet, the association of lines, and several lines of evidence support the biologic p27KIP1 with CDK2 complexes is unchanged in these relevance of this model. Mice harboring kinase-dead Cdk4 animals (26). Work examining combined loss of p15INK4b or Cyclin D1 alleles that retain p27KIP1-binding capacity and p18INK4c (24) or p27KIP1 and p18INK4c (26) in mice (Cyclin D1K112E, Cdk4D158N) display heightened CDK2 suggests that distinct mechanisms are used by each inhibitor activity (16–18) and fewer developmental defects than to control cellular proliferation. This result is in contrast to Cyclin D1 knockouts (KOs). The same observation holds the CDK inhibitor reshuffling model wherein co-deletion true for a Cyclin D1 knockin mutation incapable of binding would be predicted to concertedly promote CDK2 activity. D RB (Cyclin D1 LxCxE; ref. 19). As such, it is not surprising However, it is important to note that none of these pub- that p27KIP1 deletion can rescue the retinal hypoplasia and lications contest the fact that CDK2 inhibitors bind early mortality phenotypes of Cyclin D1-null mice (20, 21). CYCLIN D–CDK4/6 complexes and are released upon More recently, the biologic relevance of CDK inhibitor p16INK4a expression. Moreover, recent findings suggest that reshuffling has come under scrutiny. Knockin mice harbor- p16INK4a may contribute to cell-cycle regulation through ing p16INK4a-insensitive Cdk4 and Cdk6 alleles still capable additional CDK-independent mechanisms. Specifically, of binding p27KIP1 (Cdk6R31C and Cdk4R21C, respectively) expression of p16INK4a has been reported to stabilize do not display the phenotypes predicted by this model p21CIP1, and may inhibit the AUF1-dependent decay of (18, 22). The decreased p16INK4a-binding capacity of these p21CIP1, cyclin D1, and e2f1 mRNA (27, 28). As a whole, mutants should promote p27KIP1 sequestration and these data provide evidence that the cell-cycle–related func- enhanced CDK2 activity, but neither cells from the liver tions of p16INK4a may extend beyond CDK4/6 inhibition to or testes of Cdk4R21C mice show changes in the composition include the regulation of other CDK-CYCLIN targets. of CDK2–Cyclin complexes, nor do thymocytes harboring the Cdk6R31C allele (18, 22). These data suggest that, in at Transcriptional, Translational, and Epigenetic p16INK4a least a subset of cell types, the kinase activity of CDK4/6 is Regulation of predominantly responsible for proliferative control. KO To maintain tissue homeostasis and prevent cancer, the mice lacking a single CDK4/6 inhibitor (p16INK4a, p15INK4b ability of p16INK4a to inhibit cellular proliferation must be OF2 Mol Cancer Res; 12(2) February 2014 Molecular Cancer
Load more

Recommended publications
  • ` Probing the Epigenome Andrea Huston1, Cheryl H Arrowsmith1,2
    ` Probing the Epigenome Andrea Huston1, Cheryl H Arrowsmith1,2, Stefan Knapp3,4,*, Matthieu Schapira1,5,* 1. Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada 2. Princess Margaret Cancer Centre and Department of Medical Biophysics, University of Toronto , Toronto, ON M5G 1L7, Canada 3. Nuffield Department of Clinical Medicine, Target Discovery Institute, and Structural Genomic Consortium, University of Oxford, Headington, Oxford OX3 7DQ, United Kingdom 4. Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe University, D-60438 Frankfurt am Main, Germany 5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada * Correspondence: [email protected], [email protected] Epigenetic chemical probes are having a strong impact on biological discovery and target validation. Systematic coverage of emerging epigenetic target classes with these potent, selective, cell-active chemical tools will profoundly influence our understanding of the human biology and pathology of chromatin-templated mechanisms. ` Chemical probes are research-enablers Advances in genomics and proteomics methodologies in recent years have made it possible to associate thousands of genes and proteins with specific diseases, biological processes, molecular networks and pathways. However, data from these large scale initiatives alone has not translated widely into new studies on these disease-associated proteins, and the biomedical research community still tends to focus on proteins that were already known before the sequencing of the human genome1. The human kinome for instance, a target class of direct relevance to cancer and other disease areas, is a telling example: based on the number of research articles indexed in pubmed in 2011, 75% of the research activity focused on only 10% of the 518 human kinases – largely the same kinases that were the focus of research before sequencing of the human genome - while 60% of the kinome, some 300 enzymes, was virtually ignored by the community2.
    [Show full text]
  • 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.
    [Show full text]
  • 4-6 Weeks Old Female C57BL/6 Mice Obtained from Jackson Labs Were Used for Cell Isolation
    Methods Mice: 4-6 weeks old female C57BL/6 mice obtained from Jackson labs were used for cell isolation. Female Foxp3-IRES-GFP reporter mice (1), backcrossed to B6/C57 background for 10 generations, were used for the isolation of naïve CD4 and naïve CD8 cells for the RNAseq experiments. The mice were housed in pathogen-free animal facility in the La Jolla Institute for Allergy and Immunology and were used according to protocols approved by the Institutional Animal Care and use Committee. Preparation of cells: Subsets of thymocytes were isolated by cell sorting as previously described (2), after cell surface staining using CD4 (GK1.5), CD8 (53-6.7), CD3ε (145- 2C11), CD24 (M1/69) (all from Biolegend). DP cells: CD4+CD8 int/hi; CD4 SP cells: CD4CD3 hi, CD24 int/lo; CD8 SP cells: CD8 int/hi CD4 CD3 hi, CD24 int/lo (Fig S2). Peripheral subsets were isolated after pooling spleen and lymph nodes. T cells were enriched by negative isolation using Dynabeads (Dynabeads untouched mouse T cells, 11413D, Invitrogen). After surface staining for CD4 (GK1.5), CD8 (53-6.7), CD62L (MEL-14), CD25 (PC61) and CD44 (IM7), naïve CD4+CD62L hiCD25-CD44lo and naïve CD8+CD62L hiCD25-CD44lo were obtained by sorting (BD FACS Aria). Additionally, for the RNAseq experiments, CD4 and CD8 naïve cells were isolated by sorting T cells from the Foxp3- IRES-GFP mice: CD4+CD62LhiCD25–CD44lo GFP(FOXP3)– and CD8+CD62LhiCD25– CD44lo GFP(FOXP3)– (antibodies were from Biolegend). In some cases, naïve CD4 cells were cultured in vitro under Th1 or Th2 polarizing conditions (3, 4).
    [Show full text]
  • The Epigenetic Role of PHF20/MOF Histone Acetyltransferase Complex in Lung Cancer
    Aus der Klinik für Allgemein-, Viszeral-, Gefäß- und Transplantationschirurgie der Ludwig-Maximilians-Universität München (Direktor: Prof. Dr. med. Jens Werner) The Epigenetic Role of PHF20/MOF Histone Acetyltransferase Complex in Lung Cancer Dissertation zum Erwerb des Doktorgrades der Medizin an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München vorgelegt von Xiaoyan Wang Aus Shandong, China 2017 Mit der Genehmigung der Medizinischen Fakultät der Universität München Berichterstatterin: Prof. Dr. med. Christiane J. Bruns Mitberichterstatter: PD Thomas Düll Prof. Wolfgang Zimmermann Mitbetreuung durch den promovierten Mitarbeiter: Dr. rer. nat Yue Zhao Dekan: Prof. Dr. med. dent. Reinhard Hickel Tag der mündlichen Prüfung: 07. 12. 2017 Something attempted, something done. Declaration I hereby declare that the thesis is my original work. The work and data presented in the thesis were performed independently. X-ray crystallography, NMR titration experiments, NMR structure determination, and fluorescence spectroscopy were performed by our collaborator Dr. Brianna J. Klein (Department of Pharmacology, University of Colorado School of Medicine, USA) and Dr. Gaofeng Cui (Department of Biochemistry and Molecular Biology, Mayo Clinic, USA). Parts of the results have been published in the following manuscripts: Klein BJ*, Wang X*, Cui G*, Yuan C, Botuyan MV, Lin K, Lu Y, Wang X, Zhao Y, Bruns CJ, Mer G, Shi X, Kutateladze TG. PHF20 Readers Link Methylation of Histone H3K4 and p53 with H4K16 Acetylation. Cell Rep. 2016 Oct 18;17(4):1158-1170. No unauthorized data were included. Information from the literature was cited and listed in the reference. All the data presented in the thesis will not be used in any other thesis for scientific degree application.
    [Show full text]
  • Figure S17 Figure S16
    immune responseregulatingcellsurfacereceptorsignalingpathway ventricular cardiacmuscletissuedevelopment t cellactivationinvolvedinimmuneresponse intrinsic apoptoticsignalingpathway single organismalcelladhesion cholesterol biosyntheticprocess myeloid leukocytedifferentiation determination ofadultlifespan response tointerferongamma muscle organmorphogenesis endothelial celldifferentiation brown fatcelldifferentiation mitochondrion organization myoblast differentiation response toprotozoan amino acidtransport leukocyte migration cytokine production t celldifferentiation protein secretion response tovirus angiogenesis Scrt1 Tcf25 Dpf1 Sap30 Ing2 Zfp654 Sp9 Zfp263 Mxi1 Hes6 Zfp395 Rlf Ppp1r13l Snapc1 C030039L03Rik Hif1a Arrb1 Glis3 Rcor2 Hif3a Fbxo21 Dnajc21 Rest Sirt6 Foxj1 Kdm5b Ankzf1 Sos2 Plscr1 Jdp2 Rbbp8 Etv4 Msh5 Mafg Tsc22d3 Nupr1 Ddit3 Cebpg Zfp790 Atf5 Cebpb Atf3 Trim21 Irf9 Irf2 Tbx21 Stat2 Stat1 Zbp1 Irf1 aGOslimPos Ikzf3 Oasl1 Irf7 Trim30a Dhx58 Txk Rorc Rora Nr1d2 Setdb2 Vdr Vax2 Nr1d1 Foxs1 Eno1 Thap3 Nfkbil1 Edf1 Srebf1 Lbr Tead1 Zfp608 Pcx Ift57 Ssbp4 Stat3 Mxd1 Pml Ssh2 Chd7 Maf Cic Bcl3 Prkdc Mbd5 Ppfibp2 Foxp2 Tal2 Mlf1 Bcl6b Zfp827 Ikzf2 Phtf2 Bmyc Plagl2 Nfkb2 Nfkb1 Tox Nrip1 Utf1 Klf3 Plagl1 Nfkbib Spib Nfkbie Akna Rbpj Ncoa3 Id1 Tnp2 Gata3 Gata1 Pparg Id2 Epas1 Zfp280b Commons Pathway Erg GO MSigDB KEGG Hhex WikiPathways SetGene Databases Batf Aff3 Zfp266 gene modules other (hypergeometric TF, from Figure Trim24 Zbtb5 Foxo3 Aebp2 XPodNet -protein-proteininteractionsinthepodocyteexpandedbySTRING Ppp1r10 Dffb Trp53 Enrichment
    [Show full text]
  • Lysine Methylation Regulators Moonlighting Outside the Epigenome Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart
    Lysine Methylation Regulators Moonlighting outside the Epigenome Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart To cite this version: Evan Cornett, Laure Ferry, Pierre-Antoine Defossez, Scott Rothbart. Lysine Methylation Regulators Moonlighting outside the Epigenome. Molecular Cell, Elsevier, 2019, 10.1016/j.molcel.2019.08.026. hal-02359890 HAL Id: hal-02359890 https://hal.archives-ouvertes.fr/hal-02359890 Submitted on 14 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Lysine methylation regulators moonlighting outside the epigenome Evan M. Cornett1, Laure Ferry2, Pierre-Antoine Defossez2, and Scott B. RothBart1* 1Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. 2Université de Paris, Epigenetics and Cell Fate, CNRS, F-75013 Paris, France. *Correspondence: [email protected], 616-234-5367 ABSTRACT Landmark discoveries made nearly two decades ago identified known transcriptional regulators as histone lysine methyltransferases; since then the field of lysine methylation signaling has Been dominated By studies of how this small chemical posttranslational modification regulates gene expression and other chromatin-Based processes. However, recent advances in mass spectrometry-Based proteomics have revealed that histones are just a suBset of the thousands of eukaryotic proteins marked By lysine methylation.
    [Show full text]
  • Gene Networks Activated by Specific Patterns of Action Potentials in Dorsal Root Ganglia Neurons Received: 10 August 2016 Philip R
    www.nature.com/scientificreports OPEN Gene networks activated by specific patterns of action potentials in dorsal root ganglia neurons Received: 10 August 2016 Philip R. Lee1,*, Jonathan E. Cohen1,*, Dumitru A. Iacobas2,3, Sanda Iacobas2 & Accepted: 23 January 2017 R. Douglas Fields1 Published: 03 March 2017 Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life. Adaptation in the nervous system in response to external stimuli requires synthesis of new gene products in order to elicit long lasting changes in processes such as development, response to injury, learning, and memory1. Information in the environment is coded in the pattern of action-potential firing, therefore gene transcription must be regulated by the pattern of neuronal firing.
    [Show full text]
  • PDF Output of CLIC (Clustering by Inferred Co-Expression)
    PDF Output of CLIC (clustering by inferred co-expression) Dataset: Num of genes in input gene set: 8 Total number of genes: 16493 CLIC PDF output has three sections: 1) Overview of Co-Expression Modules (CEMs) Heatmap shows pairwise correlations between all genes in the input query gene set. Red lines shows the partition of input genes into CEMs, ordered by CEM strength. Each row shows one gene, and the brightness of squares indicates its correlations with other genes. Gene symbols are shown at left side and on the top of the heatmap. 2) Details of each CEM and its expansion CEM+ Top panel shows the posterior selection probability (dataset weights) for top GEO series datasets. Bottom panel shows the CEM genes (blue rows) as well as expanded CEM+ genes (green rows). Each column is one GEO series dataset, sorted by their posterior probability of being selected. The brightness of squares indicates the gene's correlations with CEM genes in the corresponding dataset. CEM+ includes genes that co-express with CEM genes in high-weight datasets, measured by LLR score. 3) Details of each GEO series dataset and its expression profile: Top panel shows the detailed information (e.g. title, summary) for the GEO series dataset. Bottom panel shows the background distribution and the expression profile for CEM genes in this dataset. Overview of Co-Expression Modules (CEMs) with Dataset Weighting Scale of average Pearson correlations Num of Genes in Query Geneset: 8. Num of CEMs: 1. 0.0 0.2 0.4 0.6 0.8 1.0 Dync2li1 Pkd2 Ift88 Dync2h1 Gli2 Pkd1 Ift46 Pafah1b1
    [Show full text]
  • Histone Peptide Microarray Screen of Chromo and Tudor Domains Defines New Histone Lysine Methylation Interactions Erin K
    Shanle et al. Epigenetics & Chromatin (2017) 10:12 DOI 10.1186/s13072-017-0117-5 Epigenetics & Chromatin RESEARCH Open Access Histone peptide microarray screen of chromo and Tudor domains defines new histone lysine methylation interactions Erin K. Shanle1†, Stephen A. Shinsky2,3,6†, Joseph B. Bridgers2, Narkhyun Bae4, Cari Sagum4, Krzysztof Krajewski2, Scott B. Rothbart5, Mark T. Bedford4* and Brian D. Strahl2,3* Abstract Background: Histone posttranslational modifications (PTMs) function to regulate chromatin structure and function in part through the recruitment of effector proteins that harbor specialized “reader” domains. Despite efforts to eluci- date reader domain–PTM interactions, the influence of neighboring PTMs and the target specificity of many reader domains is still unclear. The aim of this study was to use a high-throughput histone peptide microarray platform to interrogate 83 known and putative histone reader domains from the chromo and Tudor domain families to identify their interactions and characterize the influence of neighboring PTMs on these interactions. Results: Nearly a quarter of the chromo and Tudor domains screened showed interactions with histone PTMs by peptide microarray, revealing known and several novel methyllysine interactions. Specifically, we found that the CBX/ HP1 chromodomains that recognize H3K9me also recognize H3K23me2/3—a poorly understood histone PTM. We also observed that, in addition to their interaction with H3K4me3, Tudor domains of the Spindlin family also recog- nized H4K20me3—a previously uncharacterized interaction. Several Tudor domains also showed novel interactions with H3K4me as well. Conclusions: These results provide an important resource for the epigenetics and chromatin community on the interactions of many human chromo and Tudor domains.
    [Show full text]
  • Antibodies for Epigenetics and Gene Regulation Enabling Epigenetics Research
    antibodies for epigenetics and gene regulation Enabling Epigenetics Research 3 Chromatin Modifiers DNA Methylation Histones Transcription Regulation Highly Characterized Antibodies for Epigenetics and Gene Regulation At Active Motif, we are committed to providing the highest- polyclonal and AbFlex® recombinant antibodies are quality antibodies for studying epigenetics in the context validated for the applications you need – chromatin of histone and DNA modifications. Our antibodies are immunoprecipitation (ChIP), ChIP-Seq, Western blot, and manufactured in-house, and undergo rigorous development Immunofluorescence. and validation procedures to ensure their quality and To browse our complete list of antibodies and application performance. Our extensive, novel portfolio of monoclonal, data, please visit www.activemotif.com/abs. AbFlex® Recombinant Antibodies uniquely designed for multiple labeling methods AbFlex® antibodies are recombinant antibodies (rAbs) purification systems, and that have been generated using defined DNA sequences an avidin tag sequence to produce highly specific, reproducible antibodies. The for enzymatic biotin unique advantages of the AbFlex® antibody are its flexible conjugation using the biotin labeling and purification options. Each AbFlex® antibody ligase, BirA. contains a Sortase recognition motif (LPXTG) to covalently add fluorophores, enzymatic substrates (e.g., HRP), AbFlex is available for a peptides, DNA, drugs, or other labels to the antibody in range of Histone Markers, a directed and reproducible manner.
    [Show full text]
  • Identification of Genes and Pathways Potentially Related to PHF20 By
    Liu et al. Cancer Cell Int (2017) 17:87 DOI 10.1186/s12935-017-0459-x Cancer Cell International PRIMARY RESEARCH Open Access Identifcation of genes and pathways potentially related to PHF20 by gene expression profle analysis of glioblastoma U87 cell line Tianlong Liu1†, Tiejun Zhang6†, Feng Zhou6†, Jitao Wang2, Xiaohu Zhai1, Nan Mu3, Jongsun Park4, Minna Liu5, Wenxing Liu1, Peijin Shang1, Yi Ding1*, Aidong Wen1* and Yuwen Li1,2* Abstract Background: Glioblastoma is the most common and aggressive brain tumor associated with a poor prognosis. Plant homeodomain fnger protein 20 (PHF20) is highly expressed in primary human gliomas and its expression is associ- ated with tumor grade. However, the molecular mechanism by which PHF20 regulates glioblastoma remains poorly understood. Methods: Genome wide gene expression analysis was performed to identify diferentially expressed genes (DEGs) in U87 cells with PHF20 gene knockdown. Gene ontology (GO) and pathway enrichment analyses were performed to investigate the functions and pathways of DEGs. Pathway-net and signal-net analyses were conducted to identify the key genes and pathways related to PHF20. Results: Expression of 540 genes, including FEN1 and CCL3, were signifcantly altered upon PHF20 gene silencing. GO analysis results showed that DEGs were signifcantly enriched in small molecule metabolic and apoptotic pro- cesses. Pathway analysis indicated that DEGs were mainly involved in cancer and metabolic pathways. The MAPK, apoptosis and p53 signaling pathways were identifed as the hub pathways in the pathway network, while PLCB1, NRAS and PIK3 s were hub genes in the signaling network. Conclusions: Our fndings indicated that PHF20 is a pivotal upstream regulator.
    [Show full text]
  • Tudor-Domain Protein PHF20L1 Reads Lysine Methylated Retinoblastoma Tumour Suppressor Protein
    Cell Death and Differentiation (2017) 24, 2139–2149 OPEN Official journal of the Cell Death Differentiation Association www.nature.com/cdd Tudor-domain protein PHF20L1 reads lysine methylated retinoblastoma tumour suppressor protein Simon M Carr1, Shonagh Munro1, Cari A Sagum2, Oleg Fedorov3, Mark T Bedford2 and Nicholas B La Thangue*,1 The retinoblastoma tumour suppressor protein (pRb) classically functions to regulate early cell cycle progression where it acts to enforce a number of checkpoints in response to cellular stress and DNA damage. Methylation at lysine (K) 810, which occurs within a critical CDK phosphorylation site and antagonises a CDK-dependent phosphorylation event at the neighbouring S807 residue, acts to hold pRb in the hypo-phosphorylated growth-suppressing state. This is mediated in part by the recruitment of the reader protein 53BP1 to di-methylated K810, which allows pRb activity to be effectively integrated with the DNA damage response. Here, we report the surprising observation that an additional methylation-dependent interaction occurs at K810, but rather than the di-methyl mark, it is selective for the mono-methyl K810 mark. Binding of the mono-methyl PHF20L1 reader to methylated pRb occurs on E2F target genes, where it acts to mediate an additional level of control by recruiting the MOF acetyltransferase complex to E2F target genes. Significantly, we find that the interplay between PHF20L1 and mono-methyl pRb is important for maintaining the integrity of a pRb-dependent G1–S-phase checkpoint. Our results highlight
    [Show full text]