The role of p53 in suppression of KSHV cyclin-induced lymphomagenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 2; pp. 581 - 589
• Main Authors: VERSCHUREN, Emmy W, HODGSON, J. Graeme, GRAY, Joe W, KOGAN, Scott, JONES, Nic, EVAN, Gerard I
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-01-2004
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Crosses, Genetic; Cyclins - genetics; Cyclins - physiology; DNA Primers; Female; Genes, p53; Genotype; Herpesvirus 8, Human - pathogenicity; Kaposi's sarcoma-associated herpesvirus; Kinetics; Lymphangiogenesis - genetics; Lymphangiogenesis - physiology; Lymphoma, B-Cell - physiopathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Knockout; Mice, Transgenic; Pharmacology. Drug treatments; Plasmids; Polymerase Chain Reaction; T-Lymphocytes - radiation effects; Tumor Suppressor Protein p53 - deficiency; Tumor Suppressor Protein p53 - genetics; Tumors; Viral Proteins - genetics; Viral Proteins - physiology; Gammaherpesvirinae; Virus; Human herpesvirus 8; TP53 Gene; Herpesviridae; Suppression; Cell cycle; Cyclin; Carcinogenesis; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-1863

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.