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INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53

Item Type:Article
Title:INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53
Creators Name:Schmitt, C.A. and McCurrach, M.E. and de Stanchina, E. and Wallace-Brodeur, R.R. and Lowe, S.W.
Abstract:The INK4a/ARF locus encodes upstream regulators of the retinoblastoma and p53 tumor suppressor gene products. To compare the impact of these loci on tumor development and treatment response, the Emu-myc transgenic lymphoma model was used to generate genetically defined tumors with mutations in the INK4a/ARF, Rb, or p53 genes. Like p53 null lymphomas, INK4a/ARF null lymphomas formed rapidly, were highly invasive, displayed apoptotic defects, and were markedly resistant to chemotherapy in vitro and in vivo. Furthermore, INK4a/ARF(-/-) lymphomas displayed reduced p53 activity despite the presence of wild-type p53 genes. Consequently, INK4a/ARF and p53 mutations lead to aggressive tumors by disrupting overlapping tumor suppressor functions. These data have important implications for understanding the clinical behavior of human tumors.
Keywords:Antineoplastic Agents, Apoptosis, Drug Resistance, Genetic Enhancer Elements, myc Genes, p16 Genes, p53 Genes, Immunoglobulin Heavy Chains, Lymphoma, B-Cell, Mutation, Proteins, Tumor Suppressor Protein p14ARF, Animals, Mice
Source:Genes & Development
Publisher:Cold Spring Harbor Laboratory Press
Page Range:2670-2677
Date:15 October 1999
Official Publication:http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=317110&rendertype=abstract
PubMed:View item in PubMed

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