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

Schmitt, C. A., McCurrach, M. E., de Stanchina, E., Wallace-Brodeur, R. R., Lowe, S. W. (October 1999) INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes and Development, 13 (20). pp. 2670-7. ISSN 0890-9369 (Print)

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URL: http://www.ncbi.nlm.nih.gov/pubmed/10541553

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.

Item Type: Paper
Uncontrolled Keywords: Animals Antineoplastic Agents/pharmacology Apoptosis/genetics Drug Resistance/genetics Enhancer Elements (Genetics) Female Genes, myc Genes, p16 Genes, p53 Humans Immunoglobulin Heavy Chains/genetics Lymphoma, B-Cell/drug therapy/ etiology/ genetics Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mutation Proteins/ genetics Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S. Tumor Suppressor Protein p14ARF
Subjects: diseases & disorders > cancer > cancer types > B cell lymphoma
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types
diseases & disorders > cancer > cancer types > lymphoma
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > p53
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Kathleen Darby
Date: 15 October 1999
Date Deposited: 22 Apr 2014 17:54
Last Modified: 23 Apr 2014 18:08
PMCID: PMC317110
Related URLs:
URI: http://repository.cshl.edu/id/eprint/29850

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