2.50
Hdl Handle:
http://hdl.handle.net/10541/78173
Title:
The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis.
Authors:
Verschuren, Emmy W; Hodgson, J Graeme; Gray, Joe W; Kogan, Scott; Jones, Nic; Evan, Gerard I
Abstract:
Kaposi'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.
Affiliation:
Comprehensive Cancer Center and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.
Citation:
The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis. 2004, 64 (2):581-9 Cancer Res.
Journal:
Cancer Research
Issue Date:
15-Jan-2004
URI:
http://hdl.handle.net/10541/78173
PubMed ID:
14744772
Type:
Article
Language:
en
ISSN:
0008-5472
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
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.en
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
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