The oncogenic potential of Kaposi's sarcoma-associated herpesvirus cyclin is exposed by p53 loss in vitro and in vivo

Abstract

Expression of the Kaposi's sarcoma-associated herpesvirus (KSHV) cyclin D homolog, K cyclin, is thought to contribute to viral oncogenesis. We show that K cyclin expression in primary cells sensitizes to apoptosis and induces growth arrest, both of which are dependent on p53 but independent of E2F1 or p19(ARF). DNA synthesis, but not cytokinesis, continues in K cyclin-expressing cells, leading to multinucleation and polyploidy. Such polyploid cells exhibit pronounced centrosome amplification and consequent aneuploidy. Our data suggest that K cyclin expression leads to cytokinesis defects and polyploidy, which activates p53. However, in the absence of p53, such cells survive and expand as an aneuploid population. Corroborating these findings, in vivo Emu; K cyclin expression cooperates with p53 loss in the induction of lymphomas.

Cell death by mitotic catastrophe: a molecular definition

“…Another cancer-relevant example is provided by endopolyploid cells generated by the expression of Kcyclin (the Kaposi's sarcoma-associated herpesvirus cyclin D homologue). Such cells manifest multinucleation, polyploidy, centrosome amplification and consequent aneuploidy, provided that p53 is inactivated (Verschuren et al, 2002). When p53 is present, it is activated at the stage of polyploidy and causes cell death (Verschuren et al, 2002).…”

“…Such cells manifest multinucleation, polyploidy, centrosome amplification and consequent aneuploidy, provided that p53 is inactivated (Verschuren et al, 2002). When p53 is present, it is activated at the stage of polyploidy and causes cell death (Verschuren et al, 2002). It is possible that the downregulation of p53 by overexpressed MDM2 is also permissive for the physiological polyploidization of megakaryocytes (Datta and Long, 2002).…”

A top-notch viral oncogene

“…Surprisingly, the dramatic effects of v-cyclin on the cell cycle did not immediately translate to a strong oncogenic phenotype in vivo; expression of v-cyclin in the lymphoid compartment of mixed CBA/C57BL/6 mice led to the development of low penetrance, late onset lymphomas. 3 Undeterred, Pekkonen…”

Cyclin-Cyclin-dependent Kinase Regulatory Response Is Linked to Substrate Recognition

“…Viral cyclins drive cellular proliferation (27)(28)(29) and viral replication (30,31). Expression of the KSHV cyclin leads to genomic instability (32), and tumor formation is seen in transgenic mice expressing KSHV cyclin or a distantly related viral cyclin (29,33,34). The rhadinovirus cyclins, thought to have been pirated from the host cell (35), are homologues of cellular D-type cyclins, and like these activate the cellular catalytic subunits CDK4 and CDK6 (36).…”