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  • 1
    Publication Date: 2012-07-20
    Description: Genotypic differences greatly influence susceptibility and resistance to disease. Understanding genotype-phenotype relationships requires that phenotypes be viewed as manifestations of network properties, rather than simply as the result of individual genomic variations. Genome sequencing efforts have identified numerous germline mutations, and large numbers of somatic genomic alterations, associated with a predisposition to cancer. However, it remains difficult to distinguish background, or 'passenger', cancer mutations from causal, or 'driver', mutations in these data sets. Human viruses intrinsically depend on their host cell during the course of infection and can elicit pathological phenotypes similar to those arising from mutations. Here we test the hypothesis that genomic variations and tumour viruses may cause cancer through related mechanisms, by systematically examining host interactome and transcriptome network perturbations caused by DNA tumour virus proteins. The resulting integrated viral perturbation data reflects rewiring of the host cell networks, and highlights pathways, such as Notch signalling and apoptosis, that go awry in cancer. We show that systematic analyses of host targets of viral proteins can identify cancer genes with a success rate on a par with their identification through functional genomics and large-scale cataloguing of tumour mutations. Together, these complementary approaches increase the specificity of cancer gene identification. Combining systems-level studies of pathogen-encoded gene products with genomic approaches will facilitate the prioritization of cancer-causing driver genes to advance the understanding of the genetic basis of human cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408847/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rozenblatt-Rosen, Orit -- Deo, Rahul C -- Padi, Megha -- Adelmant, Guillaume -- Calderwood, Michael A -- Rolland, Thomas -- Grace, Miranda -- Dricot, Amelie -- Askenazi, Manor -- Tavares, Maria -- Pevzner, Samuel J -- Abderazzaq, Fieda -- Byrdsong, Danielle -- Carvunis, Anne-Ruxandra -- Chen, Alyce A -- Cheng, Jingwei -- Correll, Mick -- Duarte, Melissa -- Fan, Changyu -- Feltkamp, Mariet C -- Ficarro, Scott B -- Franchi, Rachel -- Garg, Brijesh K -- Gulbahce, Natali -- Hao, Tong -- Holthaus, Amy M -- James, Robert -- Korkhin, Anna -- Litovchick, Larisa -- Mar, Jessica C -- Pak, Theodore R -- Rabello, Sabrina -- Rubio, Renee -- Shen, Yun -- Singh, Saurav -- Spangle, Jennifer M -- Tasan, Murat -- Wanamaker, Shelly -- Webber, James T -- Roecklein-Canfield, Jennifer -- Johannsen, Eric -- Barabasi, Albert-Laszlo -- Beroukhim, Rameen -- Kieff, Elliott -- Cusick, Michael E -- Hill, David E -- Munger, Karl -- Marto, Jarrod A -- Quackenbush, John -- Roth, Frederick P -- DeCaprio, James A -- Vidal, Marc -- F32 GM095284/GM/NIGMS NIH HHS/ -- F32GM095284/GM/NIGMS NIH HHS/ -- K08 CA122833/CA/NCI NIH HHS/ -- K08 HL098361/HL/NHLBI NIH HHS/ -- K08HL098361/HL/NHLBI NIH HHS/ -- K25 HG006031/HG/NHGRI NIH HHS/ -- K25HG006031/HG/NHGRI NIH HHS/ -- P01 CA050661/CA/NCI NIH HHS/ -- P01CA050661/CA/NCI NIH HHS/ -- P50 HG004233/HG/NHGRI NIH HHS/ -- P50HG004233/HG/NHGRI NIH HHS/ -- R01 CA047006/CA/NCI NIH HHS/ -- R01 CA063113/CA/NCI NIH HHS/ -- R01 CA066980/CA/NCI NIH HHS/ -- R01 CA081135/CA/NCI NIH HHS/ -- R01 CA085180/CA/NCI NIH HHS/ -- R01 CA093804/CA/NCI NIH HHS/ -- R01 CA131354/CA/NCI NIH HHS/ -- R01 HG001715/HG/NHGRI NIH HHS/ -- R01CA047006/CA/NCI NIH HHS/ -- R01CA063113/CA/NCI NIH HHS/ -- R01CA066980/CA/NCI NIH HHS/ -- R01CA081135/CA/NCI NIH HHS/ -- R01CA085180/CA/NCI NIH HHS/ -- R01CA093804/CA/NCI NIH HHS/ -- R01CA131354/CA/NCI NIH HHS/ -- R01HG001715/HG/NHGRI NIH HHS/ -- T32 HL007208/HL/NHLBI NIH HHS/ -- T32HL007208/HL/NHLBI NIH HHS/ -- U01 CA141583/CA/NCI NIH HHS/ -- U01CA141583/CA/NCI NIH HHS/ -- England -- Nature. 2012 Jul 26;487(7408):491-5. doi: 10.1038/nature11288.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genomic Analysis of Network Perturbations Center of Excellence in Genomic Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22810586" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoviridae/genetics/metabolism/pathogenicity ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Neoplasm/*genetics ; Genome, Human/*genetics ; Herpesvirus 4, Human/genetics/metabolism/pathogenicity ; *Host-Pathogen Interactions/genetics ; Humans ; Neoplasms/*genetics/*metabolism/pathology ; Oncogenic Viruses/genetics/metabolism/*pathogenicity ; Open Reading Frames/genetics ; Papillomaviridae/genetics/metabolism/pathogenicity ; Polyomavirus/genetics/metabolism/pathogenicity ; Receptors, Notch/metabolism ; Signal Transduction ; Two-Hybrid System Techniques ; Viral Proteins/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-07-28
    Description: Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 3
    Publication Date: 2000-12-18
    Print ISSN: 0003-6951
    Electronic ISSN: 1077-3118
    Topics: Physics
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  • 4
    Publication Date: 2012-02-28
    Description: Cell cycle-dependent gene expression is often controlled on the transcriptional level. Genes like cyclin B, CDC2 and CDC25C are regulated by cell cycle-dependent element (CDE) and cell cycle genes homology region (CHR) promoter elements mainly through repression in G 0 /G 1 . It had been suggested that E2F4 binding to CDE sites is central to transcriptional regulation. However, some promoters are only controlled by a CHR. We identify the DREAM complex binding to the CHR of mouse and human cyclin B2 promoters in G 0 . Association of DREAM and cell cycle-dependent regulation is abrogated when the CHR is mutated. Although E2f4 is part of the complex, a CDE is not essential but can enhance binding of DREAM. We show that the CHR element is not only necessary for repression of gene transcription in G 0 /G 1 , but also for activation in S, G 2 and M phases. In proliferating cells, the B-myb-containing MMB complex binds the CHR of both promoters independently of the CDE. Bioinformatic analyses identify many genes which contain conserved CHR elements in promoters binding the DREAM complex. With Ube2c as an example from that screen, we show that inverse CHR sites are functional promoter elements that can bind DREAM and MMB. Our findings indicate that the CHR is central to DREAM/MMB-dependent transcriptional control during the cell cycle.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 5
    Publication Date: 2009-05-01
    Print ISSN: 0022-2461
    Electronic ISSN: 1573-4803
    Topics: Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Physics
    Published by Springer
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