25 results found
Curry E, Green I, Chapman-Rothe N, et al., 2015, Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells, CLINICAL EPIGENETICS, Vol: 7, ISSN: 1868-7083
Westerman BA, Blom M, Tanger E, et al., 2012, GFAP-Cre-mediated transgenic activation of Bmi1 results in pituitary tumors., PLoS One, Vol: 7
Bmi1 is a member of the polycomb repressive complex 1 and plays different roles during embryonic development, depending on the developmental context. Bmi1 over expression is observed in many types of cancer, including tumors of astroglial and neural origin. Although genetic depletion of Bmi1 has been described to result in tumor inhibitory effects partly through INK4A/Arf mediated senescence and apoptosis and also through INK4A/Arf independent effects, it has not been proven that Bmi1 can be causally involved in the formation of these tumors. To see whether this is the case, we developed two conditional Bmi1 transgenic models that were crossed with GFAP-Cre mice to activate transgenic expression in neural and glial lineages. We show here that these mice generate intermediate and anterior lobe pituitary tumors that are positive for ACTH and beta-endorphin. Combined transgenic expression of Bmi1 together with conditional loss of Rb resulted in pituitary tumors but was insufficient to induce medulloblastoma therefore indicating that the oncogenic function of Bmi1 depends on regulation of p16(INK4A)/Rb rather than on regulation of p19(ARF)/p53. Human pituitary adenomas show Bmi1 overexpression in over 50% of the cases, which indicates that Bmi1 could be causally involved in formation of these tumors similarly as in our mouse model.
March HN, Rust AG, Wright NA, et al., 2011, Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis., Nat Genet, Vol: 43, Pages: 1202-1209
The evolution of colorectal cancer suggests the involvement of many genes. To identify new drivers of intestinal cancer, we performed insertional mutagenesis using the Sleeping Beauty transposon system in mice carrying germline or somatic Apc mutations. By analyzing common insertion sites (CISs) isolated from 446 tumors, we identified many hundreds of candidate cancer drivers. Comparison to human data sets suggested that 234 CIS-targeted genes are also dysregulated in human colorectal cancers. In addition, we found 183 CIS-containing genes that are candidate Wnt targets and showed that 20 CISs-containing genes are newly discovered modifiers of canonical Wnt signaling. We also identified mutations associated with a subset of tumors containing an expanded number of Paneth cells, a hallmark of deregulated Wnt signaling, and genes associated with more severe dysplasia included those encoding members of the FGF signaling cascade. Some 70 genes had co-occurrence of CIS pairs, clustering into 38 sub-networks that may regulate tumor development.
Vassiliou GS, Cooper JL, Rad R, et al., 2011, Mutant nucleophosmin and cooperating pathways drive leukemia initiation and progression in mice., Nat Genet, Vol: 43, Pages: 470-475
Acute myeloid leukemia (AML) is a molecularly diverse malignancy with a poor prognosis whose largest subgroup is characterized by somatic mutations in NPM1, which encodes nucleophosmin. These mutations, termed NPM1c, result in cytoplasmic dislocation of nucleophosmin and are associated with distinctive transcriptional signatures, yet their role in leukemogenesis remains obscure. Here we report that activation of a humanized Npm1c knock-in allele in mouse hemopoietic stem cells causes Hox gene overexpression, enhanced self renewal and expanded myelopoiesis. One third of mice developed delayed-onset AML, suggesting a requirement for cooperating mutations. We identified such mutations using a Sleeping Beauty transposon, which caused rapid-onset AML in 80% of mice with Npm1c, associated with mutually exclusive integrations in Csf2, Flt3 or Rasgrp1 in 55 of 70 leukemias. We also identified recurrent integrations in known and newly discovered leukemia genes including Nf1, Bach2, Dleu2 and Nup98. Our results provide new pathogenetic insights and identify possible therapeutic targets in NPM1c+ AML.
Kool J, Uren AG, Martins CP, et al., 2010, Insertional Mutagenesis in Mice Deficient for p15(Ink4b), p16(Ink4a), p21(Cip1), and p27(Kip1) Reveals Cancer Gene Interactions and Correlations with Tumor Phenotypes, CANCER RESEARCH, Vol: 70, Pages: 520-531, ISSN: 0008-5472
Mattison J, Kool J, Uren AG, et al., 2010, Novel Candidate Cancer Genes Identified by a Large-Scale Cross-Species Comparative Oncogenomics Approach, CANCER RESEARCH, Vol: 70, Pages: 883-895, ISSN: 0008-5472
Uren A, Berns A, 2009, Jump-starting cancer gene discovery., Nat Biotechnol, Vol: 27, Pages: 251-252
Uren AG, Mikkers H, Kool J, et al., 2009, A high-throughput splinkerette-PCR method for the isolation and sequencing of retroviral insertion sites, NATURE PROTOCOLS, Vol: 4, Pages: 789-798, ISSN: 1754-2189
Csikos T, Reijmers RM, Uren AG, et al., 2008, Instant conditional transgenesis in the mouse hematopoietic compartment, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 339, Pages: 259-263, ISSN: 0022-1759
Uren AG, Kool J, Matentzoglu K, et al., 2008, Large-scale mutagenesis in p19(ARF)- and p53- Deficient mice identifies cancer genes and their collaborative networks, CELL, Vol: 133, Pages: 727-741, ISSN: 0092-8674
de Ridder J, Kool J, Uren A, et al., 2007, Co-occurrence analysis of insertional mutagenesis data reveals cooperating oncogenes., Bioinformatics, Vol: 23, Pages: i133-i141
MOTIVATION: Cancers are caused by an accumulation of multiple independent mutations that collectively deregulate cellular pathways, e.g. such as those regulating cell division and cell-death. The publicly available Retroviral Tagged Cancer Gene Database (RTCGD) contains the data of many insertional mutagenesis screens, in which the virally induced mutations result in tumor formation in mice. The insertion loci therefore indicate the location of putative cancer genes. Additionally, the presence of multiple independent insertions within one tumor hints towards a cooperation between the insertionally mutated genes. In this study we focus on the detection of statistically significant co-mutations. RESULTS: We propose a two-dimensional Gaussian Kernel Convolution method (2DGKC), a computational technique that identifies the cooperating mutations in insertional mutagenesis data. We define the Common Co-occurrence of Insertions (CCI), signifying the co-mutations that are statistically significant across all different screens in the RTCGD. Significance estimates are made on multiple scales, and the results visualized in a scale space, thereby providing valuable extra information on the putative cooperation. The multidimensional analysis of the insertion data results in the discovery of 86 statistically significant co-mutations, indicating the presence of cooperating oncogenes that play a role in tumor development. Since oncogenes may cooperate with several members of a parallel pathway, we combined the co-occurrence data with gene family information to find significant cooperations between oncogenes and families of genes. We show, for instance, the interchangeable cooperation of Myc insertions with insertions in the Pim family. AVAILABILITY: A list of the resulting CCIs is available at: http://ict.ewi.tudelft.nl/~jeroen/CCI/CCI_list.txt.
de Ridder J, Uren A, Kool J, et al., 2006, Detecting statistically significant common insertion sites in retroviral insertional mutagenesis screens., PLoS Comput Biol, Vol: 2
Retroviral insertional mutagenesis screens, which identify genes involved in tumor development in mice, have yielded a substantial number of retroviral integration sites, and this number is expected to grow substantially due to the introduction of high-throughput screening techniques. The data of various retroviral insertional mutagenesis screens are compiled in the publicly available Retroviral Tagged Cancer Gene Database (RTCGD). Integrally analyzing these screens for the presence of common insertion sites (CISs, i.e., regions in the genome that have been hit by viral insertions in multiple independent tumors significantly more than expected by chance) requires an approach that corrects for the increased probability of finding false CISs as the amount of available data increases. Moreover, significance estimates of CISs should be established taking into account both the noise, arising from the random nature of the insertion process, as well as the bias, stemming from preferential insertion sites present in the genome and the data retrieval methodology. We introduce a framework, the kernel convolution (KC) framework, to find CISs in a noisy and biased environment using a predefined significance level while controlling the family-wise error (FWE) (the probability of detecting false CISs). Where previous methods use one, two, or three predetermined fixed scales, our method is capable of operating at any biologically relevant scale. This creates the possibility to analyze the CISs in a scale space by varying the width of the CISs, providing new insights in the behavior of CISs across multiple scales. Our method also features the possibility of including models for background bias. Using simulated data, we evaluate the KC framework using three kernel functions, the Gaussian, triangular, and rectangular kernel function. We applied the Gaussian KC to the data from the combined set of screens in the RTCGD and found that 53% of the CISs do not reach the significance thresh
Uren AG, Kool J, Berns A, et al., 2005, Retroviral insertional mutagenesis: past, present and future, ONCOGENE, Vol: 24, Pages: 7656-7672, ISSN: 0950-9232
Speliotes EK, Uren A, Vaux D, et al., 2000, The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone., Mol Cell, Vol: 6, Pages: 211-223, ISSN: 1097-2765
Baculoviral IAP repeat proteins (BIRPs) may affect cell death, cell division, and tumorigenesis. The C. elegans BIRP BIR-1 was localized to chromosomes and to the spindle midzone. Embryos and fertilized oocytes lacking BIR-1 had defects in chromosome behavior, spindle midzone formation, and cytokinesis. We observed indistinguishable defects in fertilized oocytes and embryos lacking the Aurora-like kinase AIR-2. AIR-2 was not present on chromosomes in the absence of BIR-1. Histone H3 phosphorylation and HCP-1 staining, which marks kinetochores, were reduced in the absence of either BIR-1 or AIR-2. We propose that BIR-1 localizes AIR-2 to chromosomes and perhaps to the spindle midzone, where AIR-2 phosphorylates proteins that affect chromosome behavior and spindle midzone organization. The human BIRP survivin, which is upregulated in tumors, could partially substitute for BIR-1 in C. elegans. Deregulation of bir-1 promotes changes in ploidy, suggesting that similar deregulation of mammalian BIRPs may contribute to tumorigenesis.
Uren AG, O'Rourke K, Aravind L, et al., 2000, Identification of paracaspases and metacaspases: Two ancient families of caspase-like proteins, one of which plays a key role in MALT lymphoma, MOLECULAR CELL, Vol: 6, Pages: 961-967, ISSN: 1097-2765
Uren AG, Wong L, Pakusch M, et al., 2000, Survivin and the inner centromere protein INCENP show similar cell-cycle localization and gene knockout phenotype, CURRENT BIOLOGY, Vol: 10, Pages: 1319-1328, ISSN: 0960-9822
Uren AG, Beilharz T, O'Connell MJ, et al., 1999, Role for yeast inhibitor of apoptosis (IAP)-like proteins in cell division, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 96, Pages: 10170-10175, ISSN: 0027-8424
Hawkins CJ, Ekert PG, Uren AG, et al., 1998, Anti-apoptotic potential of insect cellular and viral IAPs in mammalian cells, CELL DEATH AND DIFFERENTIATION, Vol: 5, Pages: 569-576, ISSN: 1350-9047
Uren AG, Coulson EJ, Vaux DL, 1998, Conservation of baculovirus inhibitor of apoptosis repeat proteins (BIRPs) in viruses, nematodes, vertebrates and yeasts, TRENDS IN BIOCHEMICAL SCIENCES, Vol: 23, Pages: 159-162, ISSN: 0968-0004
Uren AG, Vaux DL, 1997, Viral inhibitors of apoptosis, VITAMINS AND HORMONES - ADVANCES IN RESEARCH AND APPLICATIONS, VOL 53, Vol: 53, Pages: 175-193, ISSN: 0083-6729
Vaux DL, Hawkins CJ, Uren AG, et al., 1997, Motor neurone disease and the life of motor neurones, MEDICAL JOURNAL OF AUSTRALIA, Vol: 166, Pages: 109-109, ISSN: 0025-729X
Hawkins CJ, Uren AG, Hacker G, et al., 1996, Inhibition of interleukin 1 beta-converting enzyme-mediated apoptosis of mammalian cells by baculovirus IAP, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 93, Pages: 13786-13790, ISSN: 0027-8424
Uren AG, Pakusch M, Hawkins CJ, et al., 1996, Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 93, Pages: 4974-4978, ISSN: 0027-8424
Uren AG, Vaux DL, 1996, TRAF proteins and meprins share a conserved domain, TRENDS IN BIOCHEMICAL SCIENCES, Vol: 21, Pages: 244-245, ISSN: 0968-0004
Uren AG, Vaux DL, 1996, Molecular and clinical aspects of apoptosis, PHARMACOLOGY & THERAPEUTICS, Vol: 72, Pages: 37-50, ISSN: 0163-7258
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