The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis.
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.
Verschuren
Emmy W
EW
Comprehensive Cancer Center and Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, California, USA.
Hodgson
J Graeme
JG
Gray
Joe W
JW
Kogan
Scott
S
Jones
Nic
N
Evan
Gerard I
GI
D000818:Animals; D045744:Cell Line, Tumor; D003433:Crosses, Genetic; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D005260:Female; D016158:Genes, p53; D005838:Genotype; D019288:Herpesvirus 8, Human / Q000472:pathogenicity*; D007700:Kinetics; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D016393:Lymphoma, B-Cell / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010957:Plasmids; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D014764:Viral Proteins / Q000235:genetics / Q000502:physiology*
D016213:Cyclins; D017931:DNA Primers; C483104:K cyclin protein, Herpesvirus 8, Human; D016159:Tumor Suppressor Protein p53; D014764:Viral Proteins