DOCSLIB.ORG

Evolutionarily Conserved Protein ERH Controls CENP-E Mrna Splicing

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Evolutionarily Conserved Protein ERH Controls CENP-E Mrna Splicing Evolutionarily conserved protein ERH controls CENP-E PNAS PLUS mRNA splicing and is required for the survival of KRAS mutant cancer cells Meng-Tzu Wenga,b,c, Jih-Hsiang Leea, Shu-Chen Weid, Qiuning Lia, Sina Shahamatdara, Dennis Hsua, Aaron J. Schettere, Stephen Swatkoskif, Poonam Mannang, Susan Garfieldg, Marjan Gucekf, Marianne K. H. Kima, Christina M. Annunziataa, Chad J. Creightonh, Michael J. Emanuelei, Curtis C. Harrise, Jin-Chuan Sheud, Giuseppe Giacconea, and Ji Luoa,1 aMedical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; bGraduate Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan; cFar-Eastern Memorial Hospital, Taipei 220, Taiwan; dDepartment of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan; eLaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; fProteomics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; gConfocal Microscopy Core Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; hDepartment of Medicine and Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030; and iDepartment of Genetics, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115 Edited by Bert Vogelstein, Johns Hopkins University, Baltimore, MD, and approved November 12, 2012 (received for review June 1, 2012) Cancers with Ras mutations represent a major therapeutic prob- anaphase-promoting complex (APC/C) that coordinately maintain lem. Recent RNAi screens have uncovered multiple nononcogene the fidelity of chromosome segregation (6). Symmetrical distribu- addiction pathways that are necessary for the survival of Ras mu- tion of chromosomes during mitosis is critical for genomic stability tant cells. Here, we identify the evolutionarily conserved gene en- and cell survival (8, 9). During metaphase, chromosomes con- hancer of rudimentary homolog (ERH), in which depletion causes gression from spindle poles to the metaphase midplate is driven by greater toxicity in cancer cells with mutations in the small GTPase the plus end-directed kinesin centromere protein E (CENP-E) (10). KRAS compared with KRAS WT cells. ERH interacts with the spliceo- Unattached kinetochores activate spindle assembly checkpoint some protein SNRPD3 and is required for the mRNA splicing of the proteins such as budding uninhibited by benzimidazoles 1 homolog mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E (Bub1), MAD3/BUB1-related protein kinase (BubR1), and mitotic and consequently, chromosome congression defects. Gene expres- arrest deficient 2-like protein 1 (MAD2), which in turn, inhibit the sion profiling indicates that ERH is required for the expression of activity of APC/C to delay anaphase onset until all sister chromatids multiple cell cycle genes, and the gene expression signature result- are bioriented and properly attached to opposite spindle poles (11). ing from ERH down-regulation inversely correlates with KRAS sig- Many mitotic proteins are degraded by APC/C on mitotic exit. natures. Clinically, tumor ERH expression is inversely associated CENP-E is one such protein, and it is degraded on mitosis exit and with survival of colorectal cancer patients whose tumors harbor resynthesized in the next S-phase (12). Thus, the proper expression KRAS mutations. Together, these findings identify a role of ERH in and turnover of CENP-E during each cell cycle is necessary for CELL BIOLOGY mRNA splicing and mitosis, and they provide evidence that KRAS chromosome congression and genomic stability (13, 14). mutant cancer cells are dependent on ERH for their survival. In this report, we identify a candidate Ras synthetic lethal gene, enhancer of rudimentary homolog (ERH). ERH is a highly synthetic lethality | spliceosome conserved gene originally identified in Drosophila (15), and it has been implicated to play a role in nuclear gene expression (16– he Ras family of small GTPases is mutated in a significant 18). Here, we show that ERH interacts with the Sm protein Tfraction of human cancers, with high frequencies of muta- SNRPD3, and it plays a critical role in the mRNA splicing and tions in v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog therefore, expression of CENP-E. KRAS mutant colorectal (KRAS) found in colon, lung, and pancreatic cancers (1–4). Ras cancer (CRC) cells are more sensitive to the depletion of ERH proteins are activated by growth factor receptors, and they, in turn, protein. Consistent with this finding, low ERH expression is as- activate a number of downstream effector pathways to coordinate sociated with better survival in cancer patients whose tumors cell proliferation, survival, and migration. Somatic mutations in harbor KRAS mutations. Our findings suggest that targeted in- Ras frequently lead to its constitutive activation, which in turn, activation of splicing machinery could be exploited to thera- drives malignant growth. Cancer cells harboring mutations in peutically restrict the malignancy of Ras-driven cancer. KRAS often exhibit the classic behavior of oncogene addiction: they become dependent on the KRAS oncogene for growth and Results survival and therefore, are hypersensitive to the loss of KRAS Ras Mutant Cells Are Hypersensitive to ERH Depletion. We identified protein (5). Efforts to pharmacologically inactivate mutant KRAS ERH as a candidate KRAS synthetic lethal gene from a genome- have been unsuccessful thus far. To identify additional genetic de- pendencies in Ras mutant cells, we previously conducted a genome- wide shRNA synthetic lethal screen in isogenic KRAS mutant and fi Author contributions: M.-T.W. and J.L. designed research; M.-T.W., J.-H.L., S.-C.W., Q.L., WTcells(6).Inthisscreen,weidenti ed a surprisingly diverse set of S. Shahamatdar, D.H., and S. Swatkoski performed research; S.-C.W., S. Swatkoski, P.M., genes whose depletion causes greater toxicity in KRAS mutant cells S.G., M.G., C.M.A., C.C.H., J.-C.S., and G.G. contributed new reagents/analytic tools; compared with KRAS WT cells. Surprisingly, many of these genes M.-T.W., J.-H.L., A.J.S., M.K.H.K, C.J.C., M.J.E., G.G., and J.L. analyzed the data; and do not directly partake in the Ras signaling network, but rather, they M.-T.W., J.H.L., and J.L. wrote the paper. act to maintain cell viability by alleviating the stress phenotypes in The authors declare no conflict of interest. cancer cells. We, therefore, proposed the concept of nononcogene This article is a PNAS Direct Submission. addiction to explain the heightened dependency of Ras mutant cells Freely available online through the PNAS open access option. on stress relief pathways for survival (7). 1To whom correspondence should be addressed. E-mail: [email protected]. In the aforementioned screen, we identified genetic interactions See Author Summary on page 21192 (volume 109, number 52). between mutant KRAS and a network of mitotic genes, including This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. the mitotic kinase polo-like kinase 1 (PLK1) and the E3 ligase 1073/pnas.1207673110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1207673110 PNAS | Published online December 10, 2012 | E3659–E3667 Downloaded by guest on October 2, 2021 − wide RNAi screen (6). ERH is a protein with 104 aa, and its breviated as KRAS mutant line, and the KRAS /wt derivative molecular function is poorly understood. To validate the genetic cells are abbreviated as the KRAS WT line. We found that, in interaction between ERH and the KRAS oncogene, we first each isogenic pair, the KRAS mutant cells showed less viability tested an shRNA targeting ERH that scored in the screen using on ERH knockdown compared with their respective KRAS WT DLD-1 and HCT116 isogenic cells that are either WT or mutant counterpart (Fig. 1A). Western blot and quantitative RT-PCR for KRAS. These isogenic cells were derived by targeted deletion (RT-qPCR) revealed a partial knockdown of ERH by this of the mutant KRASG13D allele (6, 19, 20). For simplicity, the shRNA (Fig. 1B and Fig. S1A). Because this shRNA is the only parental cell line with KRASG13D/wt genotype is hereafter ab- effective shRNA against ERH in our library, we identified two Fig. 1. Synthetic lethal interactions between ERH and the KRAS oncogene. (A) DLD-1 and HCT116 KRAS mutant cells show less viability compared with their respective WT control after retroviral ERH shRNA infection. Cell viability was assessed 4 d post-shRNA infection (error bars indicated SD of three independent experiments in all figures unless otherwise indicated). (B) Confirmation of ERH protein knockdown by ERH shRNA at 4 d post-shRNA infection. The number below each band indicates relative ERH protein level. (C) DLD-1 and HCT116 KRAS mutant cells show less viability compared with their respective KRAS WT control after ERH siRNA transfection. Cell viability was assessed 3 d post-siRNA transfection (assessment was the same for all siRNA viability experiment unless otherwise stated). (D) Confirmation of ERH protein knockdown by ERH siRNAs at 3 d post-siRNA transfection. (E) An HA-ERH cDNA rescue construct lacking the UTR regions of endogenous ERH remains sensitive to siERH-3, but it is resistant to siERH-5, which was confirmed by Western blot. (F) Stable expression of HA-ERH rescues the toxicity of siERH 5 in both DLD-1 and HCT116 KRAS mutant cells. (G) ERH depletion strongly decreases the ability of DLD-1 KRAS mutant cells to form colonies in soft agarose. Cells were transfected with indicated siRNAs and plated in soft agarose. Colonies were counted 14 d later. (H)Correlationof sensitivities to KRAS and ERH siRNAs in a panel of KRAS mutant (SW1116, SW620, SW403, LS123, and LOVO) and WT (RKO, CACO2, and SW48) CRC cell lines.
Load more

Recommended publications
  • Haplotypes Are Associated with Susceptibility To
    www.nature.com/scientificreports OPEN Serpin peptidase inhibitor (SERPINB5) haplotypes are associated with susceptibility to Received: 02 March 2016 Accepted: 05 May 2016 hepatocellular carcinoma Published: 25 May 2016 Shun-Fa Yang1,2, Chao-Bin Yeh3,4, Ying-Erh Chou2,5, Hsiang-Lin Lee1,6 & Yu-Fan Liu7,8 Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related death worldwide. The serpin peptidase inhibitor SERPINB5 is a tumour-suppressor gene that promotes the development of various cancers in humans. However, whether SERPINB5 gene variants play a role in HCC susceptibility remains unknown. In this study, we genotyped 6 SNPs of the SERPINB5 gene in an independent cohort from a replicate population comprising 302 cases and 590 controls. Additionally, patients who had at least one rs2289520 C allele in SERPINB5 tended to exhibit better liver function than patients with genotype GG (Child-Pugh grade A vs. B or C; P = 0.047). Next, haplotype blocks were reconstructed according to the linkage disequilibrium structure of the SERPINB5 gene. A haplotype “C-C-C” (rs17071138 + rs3744941 + rs8089204) in SERPINB5-correlated promoter showed a significant association with an increased HCC risk (AOR = 1.450; P = 0.031). Haplotypes “T-C-A” and “C-C-C” (rs2289519 + rs2289520 + rs1455555) located in the SERPINB5 coding region had a decreased (AOR = 0.744; P = 0.031) and increased (AOR = 1.981; P = 0.001) HCC risk, respectively. Finally, an additional integrated in silico analysis confirmed that these SNPs affectedSERPINB5 expression and protein stability, which significantly correlated with tumour expression and subsequently with tumour development and aggressiveness.
    [Show full text]
  • Downloaded 10 April 2020)
    Breeze et al. Genome Medicine (2021) 13:74 https://doi.org/10.1186/s13073-021-00877-z RESEARCH Open Access Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci Charles E. Breeze1,2,3* , Anna Batorsky4, Mi Kyeong Lee5, Mindy D. Szeto6, Xiaoguang Xu7, Daniel L. McCartney8, Rong Jiang9, Amit Patki10, Holly J. Kramer11,12, James M. Eales7, Laura Raffield13, Leslie Lange6, Ethan Lange6, Peter Durda14, Yongmei Liu15, Russ P. Tracy14,16, David Van Den Berg17, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed MESA Multi-Omics Working Group, Kathryn L. Evans8, William E. Kraus15,18, Svati Shah15,18, Hermant K. Tiwari10, Lifang Hou19,20, Eric A. Whitsel21,22, Xiao Jiang7, Fadi J. Charchar23,24,25, Andrea A. Baccarelli26, Stephen S. Rich27, Andrew P. Morris28, Marguerite R. Irvin29, Donna K. Arnett30, Elizabeth R. Hauser15,31, Jerome I. Rotter32, Adolfo Correa33, Caroline Hayward34, Steve Horvath35,36, Riccardo E. Marioni8, Maciej Tomaszewski7,37, Stephan Beck2, Sonja I. Berndt1, Stephanie J. London5, Josyf C. Mychaleckyj27 and Nora Franceschini21* Abstract Background: DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods: The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays.
    [Show full text]
  • Evolutionarily Conserved Protein ERH Controls CENP-E Mrna Splicing and Is Required for the Survival of KRAS Mutant Cancer Cells
    Evolutionarily conserved protein ERH controls CENP-E PNAS PLUS mRNA splicing and is required for the survival of KRAS mutant cancer cells Meng-Tzu Wenga,b,c, Jih-Hsiang Leea, Shu-Chen Weid, Qiuning Lia, Sina Shahamatdara, Dennis Hsua, Aaron J. Schettere, Stephen Swatkoskif, Poonam Mannang, Susan Garfieldg, Marjan Gucekf, Marianne K. H. Kima, Christina M. Annunziataa, Chad J. Creightonh, Michael J. Emanuelei, Curtis C. Harrise, Jin-Chuan Sheud, Giuseppe Giacconea, and Ji Luoa,1 aMedical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; bGraduate Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan; cFar-Eastern Memorial Hospital, Taipei 220, Taiwan; dDepartment of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan; eLaboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; fProteomics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; gConfocal Microscopy Core Facility, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; hDepartment of Medicine and Dan L. Duncan Cancer Center Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030; and iDepartment of Genetics, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA 02115 Edited by Bert Vogelstein, Johns Hopkins University, Baltimore, MD, and approved November 12, 2012 (received for review June 1, 2012) Cancers with Ras mutations represent a major therapeutic prob- anaphase-promoting complex (APC/C) that coordinately maintain lem. Recent RNAi screens have uncovered multiple nononcogene the fidelity of chromosome segregation (6). Symmetrical distribu- addiction pathways that are necessary for the survival of Ras mu- tion of chromosomes during mitosis is critical for genomic stability tant cells.
    [Show full text]
  • Kidney V-Atpase-Rich Cell Proteome Database
    A comprehensive list of the proteins that are expressed in V-ATPase-rich cells harvested from the kidneys based on the isolation by enzymatic digestion and fluorescence-activated cell sorting (FACS) from transgenic B1-EGFP mice, which express EGFP under the control of the promoter of the V-ATPase-B1 subunit. In these mice, type A and B intercalated cells and connecting segment principal cells of the kidney express EGFP. The protein identification was performed by LC-MS/MS using an LTQ tandem mass spectrometer (Thermo Fisher Scientific). For questions or comments please contact Sylvie Breton ([email protected]) or Mark A. Knepper ([email protected]).
    [Show full text]
  • Genome-Wide Analysis of Organ-Preferential Metastasis of Human Small Cell Lung Cancer in Mice
    Vol. 1, 485–499, May 2003 Molecular Cancer Research 485 Genome-Wide Analysis of Organ-Preferential Metastasis of Human Small Cell Lung Cancer in Mice Soji Kakiuchi,1 Yataro Daigo,1 Tatsuhiko Tsunoda,2 Seiji Yano,3 Saburo Sone,3 and Yusuke Nakamura1 1Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan; 2Laboratory for Medical Informatics, SNP Research Center, Riken (Institute of Physical and Chemical Research), Tokyo, Japan; and 3Department of Internal Medicine and Molecular Therapeutics, The University of Tokushima School of Medicine, Tokushima, Japan Abstract Molecular interactions between cancer cells and their Although a number of molecules have been implicated in microenvironment(s) play important roles throughout the the process of cancer metastasis, the organ-selective multiple steps of metastasis (5). Blood flow and other nature of cancer cells is still poorly understood. To environmental factors influence the dissemination of cancer investigate this issue, we established a metastasis model cells to specific organs (6). However, the organ specificity of in mice with multiple organ dissemination by i.v. injection metastasis (i.e., some organs preferentially permit migration, of human small cell lung cancer (SBC-5) cells. We invasion, and growth of specific cancer cells, but others do not) analyzed gene-expression profiles of 25 metastatic is a crucial determinant of metastatic outcome, and proteins lesions from four organs (lung, liver, kidney, and bone) involved in the metastatic process are considered to be using a cDNA microarray representing 23,040 genes and promising therapeutic targets. extracted 435 genes that seemed to reflect the organ More than a century ago, Stephen Paget suggested that the specificity of the metastatic cells and the cross-talk distribution of metastases was not determined by chance, but between cancer cells and microenvironment.
    [Show full text]
  • Serine-Phosphorylated STAT3 Promotes Tumorigenesis Via Modulation of RNA Polymerase Transcriptional Activity
    Author Manuscript Published OnlineFirst on September 3, 2019; DOI: 10.1158/0008-5472.CAN-19-0974 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Serine-phosphorylated STAT3 promotes tumorigenesis via modulation of RNA polymerase transcriptional activity Jesse J. Balic1,2, Daniel J. Garama2,3,#, Mohamed I. Saad1,2,#, Liang Yu1,2, Alison C. West1,2, Alice J. West1,2, Thaleia Livis1,2, Prithi S. Bhathal2, Daniel J. Gough2,3,* and Brendan J. Jenkins1,2,* 1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria, 3168, Australia. 2Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, 3800, Australia. 3Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia. #Daniel J. Garama and Mohamed I. Saad contributed equally. *To whom correspondence should be addressed: Brendan J. Jenkins, Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia. Tel +61 3 8572 2740; E-mail [email protected]. Daniel J. Gough, Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, Victoria 3168, Australia. Tel +61 3 8572 2710; E-mail [email protected] Running title: STAT3 serine phosphorylation promotes gastric cancer 1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 3, 2019; DOI: 10.1158/0008-5472.CAN-19-0974 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
    [Show full text]
  • Estrogen Receptor A^ Negative Breast Cancer Tissues Express
    Cancer Prevention Estrogen Receptor A ^ Negative Breast Cancer Tissues Express Significant Levels of Estrogen-Independent Transcription Factors, ERB1andERB5: Potential Molecular Targets for Chemoprevention Indira Poola,1Suzanne A.W. Fuqua,4 Robert L. DeWitty,2 Jessy Abraham,1 Josephine J. Marshallack,3 and Aiyi Liu5 Abstract We have investigated the expression of two estrogen receptor h (ERh) isoforms, ERh1and ERh5, which activate gene transcription independent of estrogen or growth factors, in ERa-negative breast cancer tissues.We report here, for the first time, that ERa-negative tissues express signifi- cant levels of ERh1andERh5, and their expression levels are not different fromlevels in ERa - positive tumors. However, significant differences exist between the two racial groups, African American and Caucasian, in that the patients from the former group express higher levels of ERh1and ERh5 but not ERa.These two transcription factors could be potential molecular targets for designing chemopreventive drugs to treat ERa-negative breast cancers. It is now well accepted that unopposed stimulation of breast isoforms, ERh1 and ERh5, which can activate the same genes as epithelial cells by the natural hormone, estrogen, plays a major the ERa, independent of estrogen (1), are expressed in these role in the advancement of breast cancers. Although the exact tissues. The rational for our study is that once we establish the mechanism(s) by which estrogen causes breast cancer progres- expression of ERh in ERa-negative tissues, a novel line of ERh- sion are not known, several studies have established that targeted drugs could be designed to treat ERa-negative tumors increased gene transcription by estrogen-activated transcription similar to ERa blockers for ERa-positive tumors.
    [Show full text]
  • ERH Proteins: Connecting RNA Processing to Tumorigenesis? Marc Graille, Mathieu Rougemaille
    ERH proteins: connecting RNA processing to tumorigenesis? Marc Graille, Mathieu Rougemaille To cite this version: Marc Graille, Mathieu Rougemaille. ERH proteins: connecting RNA processing to tumorigenesis?. Current Genetics, Springer Verlag, 2020, 66 (4), pp.689-692. 10.1007/s00294-020-01065-z. hal- 02503603 HAL Id: hal-02503603 https://hal-polytechnique.archives-ouvertes.fr/hal-02503603 Submitted on 10 Nov 2020 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. ERH proteins: connecting RNA processing to tumorigenesis? Marc Graille1 and Mathieu Rougemaille2 1Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole polytechnique, Institut Po- lytechnique de Paris, F-91128 Palaiseau, France 2 Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198, Gif-sur-Yvette, France Abstract With the development of -omics approaches, the scientific community is now submerged by a wealth of information that can be used to analyze various parameters: the degree of protein se- quence conservation, protein 3D structures as well as RNA and protein expression levels in various benign and tumor tissues, during organism development or upon exposure to chemicals such as en- docrine disrupters. However, if such information can be used to identify genes with potentially im- portant biological function, additional studies are needed to deeply characterize their cellular func- tion in model organisms.
    [Show full text]
  • Enhancer of Rudimentary Homolog Regulates DNA Damage Response In
    OPEN Enhancer of rudimentary homolog SUBJECT AREAS: regulates DNA damage response in LIVER CANCER CANCER THERAPY hepatocellular carcinoma Meng-Tzu Weng1,2, Tzu-Hsun Tung3, Jih-Hsiang Lee4, Shu-Chen Wei5, Hang-Li Lin5, Yu-Jung Huang3, Received Jau-Min Wong5, Ji Luo6 & Jin-Chuan Sheu5 20 October 2014 Accepted 1Graduate Institute of Clinical Medicine, National Taiwan University, Taipei 100, Taiwan, 2Far-Eastern Memorial Hospital, New 2 March 2015 Taipei 220, Taiwan, 3Liver Disease Prevention and Treatment Research Foundation, Taipei 100, Taiwan, 4Clinical Trial Center, Taipei 100, Taiwan, 5Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei 100, Published Taiwan, 6Cancer Systems Biology Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, NIH Bethesda, 9 April 2015 MD 20892, USA. Correspondence and We previously demonstrated that the enhancer of rudimentary homolog (ERH) gene is required for the expression of multiple cell cycle and DNA damage response (DDR) genes. The present study investigated the requests for materials role of ERH and its target DNA damage repair genes in hepatocellular carcinoma cells. We observed positive should be addressed to correlation between ERH and ataxia telangiectasia and Rad3 related (ATR) expression in liver tissues. J.-C.S. (jcsheu@ntu. Expression of ERH, ATR as well as checkpoint kinase 1 (CHK1) were higher in HCCs than in normal liver edu.tw) tissues. Knocking-down ERH augmented ultraviolet light induced DNA damage in HepG2 cells. ATR protein level is reduced upon ERH depletion as a result of defect in the splicing of ATR mRNA. Consequently, the ATR effector kinase Chk1 failed to be phosphorylated upon ultraviolet light or hydroxyurea treatment in ERH knocked-down HepG2 cells.
    [Show full text]
  • Multimodal, Multidimensional Models of Mouse Brain
    NIH Public Access Author Manuscript Epilepsia. Author manuscript; available in PMC 2011 October 13. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Epilepsia. 2007 ; 48(Suppl 4): 75±81. doi:10.1111/j.1528-1167.2007.01244.x. Multimodal, Multidimensional Models of Mouse Brain Allan J. MacKenzie-Graham*, Erh-Fang Lee*, Ivo D. Dinov*, Heng Yuan*, Russell E. Jacobs†, and Arthur W. Toga* *Laboratory of Neuro Imaging, University of California, Los Angeles, California, U.S.A †Beckman Institute, California Institute of Technology, Pasadena, California, U.S.A Summary Naturally occurring mutants and genetically manipulated strains of mice are widely used to model a variety of human diseases. Atlases are an invaluable aid in understanding the impact of such manipulations by providing a standard for comparison and to facilitate the integration of anatomic, genetic, and physiologic observations from multiple subjects and experiments. We have developed digital atlases of the C57BL/6J mouse brain (adult and neonate) as comprehensive frameworks for storing and accessing the myriad types of information about the mouse brain. Along with raw and annotated images, these contain database management systems and a set of tools for comparing information from different techniques and different animals. Each atlas establishes a canonical representation of the mouse brain and provides the tools for the manipulation and analysis of new data. We describe both these atlases and discuss how they may be put to use in organizing and analyzing data from mouse models of epilepsy. Keywords Anatomy; Atlas; Neonatal; Probabilistic Historically, atlas construction comprised sectioning, staining, and recording of photomicrographs along with their descriptions within a Cartesian coordinate system.
    [Show full text]
  • Table S1. 103 Ferroptosis-Related Genes Retrieved from the Genecards
    Table S1. 103 ferroptosis-related genes retrieved from the GeneCards. Gene Symbol Description Category GPX4 Glutathione Peroxidase 4 Protein Coding AIFM2 Apoptosis Inducing Factor Mitochondria Associated 2 Protein Coding TP53 Tumor Protein P53 Protein Coding ACSL4 Acyl-CoA Synthetase Long Chain Family Member 4 Protein Coding SLC7A11 Solute Carrier Family 7 Member 11 Protein Coding VDAC2 Voltage Dependent Anion Channel 2 Protein Coding VDAC3 Voltage Dependent Anion Channel 3 Protein Coding ATG5 Autophagy Related 5 Protein Coding ATG7 Autophagy Related 7 Protein Coding NCOA4 Nuclear Receptor Coactivator 4 Protein Coding HMOX1 Heme Oxygenase 1 Protein Coding SLC3A2 Solute Carrier Family 3 Member 2 Protein Coding ALOX15 Arachidonate 15-Lipoxygenase Protein Coding BECN1 Beclin 1 Protein Coding PRKAA1 Protein Kinase AMP-Activated Catalytic Subunit Alpha 1 Protein Coding SAT1 Spermidine/Spermine N1-Acetyltransferase 1 Protein Coding NF2 Neurofibromin 2 Protein Coding YAP1 Yes1 Associated Transcriptional Regulator Protein Coding FTH1 Ferritin Heavy Chain 1 Protein Coding TF Transferrin Protein Coding TFRC Transferrin Receptor Protein Coding FTL Ferritin Light Chain Protein Coding CYBB Cytochrome B-245 Beta Chain Protein Coding GSS Glutathione Synthetase Protein Coding CP Ceruloplasmin Protein Coding PRNP Prion Protein Protein Coding SLC11A2 Solute Carrier Family 11 Member 2 Protein Coding SLC40A1 Solute Carrier Family 40 Member 1 Protein Coding STEAP3 STEAP3 Metalloreductase Protein Coding ACSL1 Acyl-CoA Synthetase Long Chain Family Member 1 Protein
    [Show full text]
  • Host Protein Interactions
    scientificscientificreport report Structure homology and interaction redundancy for discovering virus–host protein interactions Benoıˆt de Chassey 1,Laure`ne Meyniel-Schicklin 2,3, Anne Aublin-Gex 2,3, Vincent Navratil 2,3,w, Thibaut Chantier 2,3, Patrice Andre´1,2,3 &VincentLotteau2,3+ 1Hospices Civils de Lyon, Hoˆpital de la Croix-Rousse, Laboratoire de virologie, Lyon , 2Inserm, U1111, Lyon , and 3Universite´ de Lyon, Lyon, France Virus–host interactomes are instrumental to understand global purification coupled to mass spectrometry, led to the publication perturbations of cellular functions induced by infection and of the first virus–host interactomes [3–4]. Although incorporation discover new therapies. The construction of such interactomes is, of data from different methods or variation of the same method [5] however, technically challenging and time consuming. Here we has improved the quality of the data sets, diversification of describe an original method for the prediction of high-confidence methods is still clearly needed to generate high-quality interactions between viral and human proteins through comprehensive virus–host interactomes. In addition, regarding a combination of structure and high-quality interactome data. the size of host genome and the huge diversity of viruses, millions Validation was performed for the NS1 protein of the influenza of binary interactions remain to be tested. Therefore, accurate and virus, which led to the identification of new host factors that rapid methods for the identification of cellular interactors control viral replication. controlling viral replication is a major issue and a crucial step Keywords: interactome; prediction; protein interaction; towards the selection of original therapeutic targets and drug structure; virus development.
    [Show full text]