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dc.contributor.authorVerschuren, Emmy W
dc.contributor.authorHodgson, J Graeme
dc.contributor.authorGray, Joe W
dc.contributor.authorKogan, Scott
dc.contributor.authorJones, Nic
dc.contributor.authorEvan, Gerard I
dc.date.accessioned2009-08-21T11:23:27Z
dc.date.available2009-08-21T11:23:27Z
dc.date.issued2004-01-15
dc.identifier.citationThe role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. 2004, 64 (2):581-9 Cancer Res.en
dc.identifier.issn0008-5472
dc.identifier.pmid14744772
dc.identifier.urihttp://hdl.handle.net/10541/78173
dc.description.abstractKaposi's sarcoma-associated herpesvirus (KSHV) encodes a cyclin D homolog, K cyclin, that is thought to promote viral oncogenesis. However, expression of K cyclin in cultured cells not only triggers cell cycle progression but also engages the p53 tumor suppressor pathway, which probably restricts the oncogenic potential of K cyclin. Therefore, to assess the tumorigenic properties of K cyclin in vivo, we transgenically targeted expression of K cyclin to the B and T lymphocyte compartments via the E micro promoter/enhancer. Around 17% of E micro -K cyclin animals develop lymphoma by 9 months of age, and all such lymphomas exhibit loss of p53. A critical role of p53 in suppressing K cyclin-induced lymphomagenesis was confirmed by the greatly accelerated onset of B and T lymphomagenesis in all E micro -K cyclin/p53(-/-) mice. However, absence of p53 did not appear to accelerate K cyclin-induced lymphomagenesis by averting apoptosis: E micro -K cyclin/p53(-/-) end-stage lymphomas contained abundant apoptotic cells, and transgenic E micro -K cyclin/p53(-/-) lymphocytes in vitro were not measurably protected from DNA damage-induced apoptosis compared with E micro -K cyclin/p53(wt) cells. Notably, whereas aneuploidy was frequently evident in pre-lymphomatous tissues, end-stage E micro -K cyclin/p53(-/-) tumors showed a near-diploid DNA content with no aberrant centrosome numbers. Nonetheless, such tumor cells did harbor more restricted genomic alterations, such as single-copy chromosome losses or gains or high-level amplifications. Together, our data support a model in which K cyclin-induced genome instability arises early in the pre-tumorigenic lymphocyte population and that loss of p53 licenses subsequent expansion of tumorigenic clones.
dc.language.isoenen
dc.subjectCell Line Tumouren
dc.subjectTumour Suppressor Protein p53en
dc.subject.meshAnimals
dc.subject.meshCell Line, Tumor
dc.subject.meshCrosses, Genetic
dc.subject.meshCyclins
dc.subject.meshDNA Primers
dc.subject.meshFemale
dc.subject.meshGenes, p53
dc.subject.meshGenotype
dc.subject.meshHerpesvirus 8, Human
dc.subject.meshKinetics
dc.subject.meshLymphangiogenesis
dc.subject.meshLymphoma, B-Cell
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Inbred CBA
dc.subject.meshMice, Knockout
dc.subject.meshMice, Transgenic
dc.subject.meshPlasmids
dc.subject.meshPolymerase Chain Reaction
dc.subject.meshT-Lymphocytes
dc.subject.meshTumor Suppressor Protein p53
dc.subject.meshViral Proteins
dc.titleThe role of p53 in suppression of KSHV cyclin-induced lymphomagenesis.en
dc.typeArticleen
dc.contributor.departmentComprehensive Cancer Center and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.en
dc.identifier.journalCancer Researchen
html.description.abstractKaposi's sarcoma-associated herpesvirus (KSHV) encodes a cyclin D homolog, K cyclin, that is thought to promote viral oncogenesis. However, expression of K cyclin in cultured cells not only triggers cell cycle progression but also engages the p53 tumor suppressor pathway, which probably restricts the oncogenic potential of K cyclin. Therefore, to assess the tumorigenic properties of K cyclin in vivo, we transgenically targeted expression of K cyclin to the B and T lymphocyte compartments via the E micro promoter/enhancer. Around 17% of E micro -K cyclin animals develop lymphoma by 9 months of age, and all such lymphomas exhibit loss of p53. A critical role of p53 in suppressing K cyclin-induced lymphomagenesis was confirmed by the greatly accelerated onset of B and T lymphomagenesis in all E micro -K cyclin/p53(-/-) mice. However, absence of p53 did not appear to accelerate K cyclin-induced lymphomagenesis by averting apoptosis: E micro -K cyclin/p53(-/-) end-stage lymphomas contained abundant apoptotic cells, and transgenic E micro -K cyclin/p53(-/-) lymphocytes in vitro were not measurably protected from DNA damage-induced apoptosis compared with E micro -K cyclin/p53(wt) cells. Notably, whereas aneuploidy was frequently evident in pre-lymphomatous tissues, end-stage E micro -K cyclin/p53(-/-) tumors showed a near-diploid DNA content with no aberrant centrosome numbers. Nonetheless, such tumor cells did harbor more restricted genomic alterations, such as single-copy chromosome losses or gains or high-level amplifications. Together, our data support a model in which K cyclin-induced genome instability arises early in the pre-tumorigenic lymphocyte population and that loss of p53 licenses subsequent expansion of tumorigenic clones.


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