The Role of p53 in Suppression of KSHV Cyclin-induced Lymphomagenesis

Emmy W. Verschuren, J. Graeme Hodgson, Joe W. Gray, Scott Kogan, Nic Jones, Gerard I. Evan

Research output: Contribution to journalArticle

68 Scopus citations

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 pro-gression 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 Eμ promoter/enhancer. Around 17% of Eμ-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 Eμ-K cyclin/p53-/- mice. However, absence of p53 did not appear to accelerate K cyclin-induced lymphomagenesis by averting apoptosis: Eμ-K cyclin/p53-/- end-stage lymphomas contained abundant apoptotic cells, and transgenic Eμ-K cyclin/p53-/- lymphocytes in vitro were not measurably protected from DNA damage-induced apoptosis compared with Eμ-K cyclin/p53wt cells. Notably, whereas aneuploidy was frequently evident in pre-lymphomatous tissues, end-stage Eμ-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.

Original languageEnglish (US)
Pages (from-to)581-589
Number of pages9
JournalCancer Research
Volume64
Issue number2
DOIs
StatePublished - Jan 15 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Verschuren, E. W., Hodgson, J. G., Gray, J. W., Kogan, S., Jones, N., & Evan, G. I. (2004). The Role of p53 in Suppression of KSHV Cyclin-induced Lymphomagenesis. Cancer Research, 64(2), 581-589. https://doi.org/10.1158/0008-5472.CAN-03-1863