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

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

Regulation of Microfilament Organization by Kaposi Sarcoma-associated Herpes Virus-cyclin·CDK6 Phosphorylation of Caldesmon

“…The Kaposi sarcoma herpes virus (KSHV) or human herpes virus 8 (HHV8), a human tumor virus associated with the development of Kaposi sarcoma and several lymphoid malignancies in immunocompromised individuals (4 -6), encodes a cyclin (K-cyclin) that is thought to have descended from cellular D-type cyclins based on co-linearity and sequence identity. Strong evidence from transgenic mouse models suggests that K-cyclin contributes significantly to the oncogenic process elicited by this virus (7,8). D-type cyclins are recognized for their involvement in human oncogenesis (9) and K-cyclin shares their ability to activate the closely related cellular CDK4 and CDK6 and hence phosphorylate and inactivate the retinoblastoma tumor suppressor protein (Rb) (10).…”

The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma

“…The LANA transgenic mice developed here will allow us to elucidate the molecular mechanism of LANA within the appropriate cellular lineage in vivo, as well as the effect of secondary growth stimuli, due to exogenous or other viral oncogenes such as KSHV's cyclin-D homolog, which as a transgene can cause B and T cell lymphomas in the absence of p53 (42). In addition this model will be useful to test novel therapies against KSHV lymphomas.…”

Analysis of EphA2 expression and mutant p53 in ovarian carcinoma

“…[34][35][36][37][38][39] Within the context of the present study, the relationships between EphA2, p53, and clinical outcome raise interesting questions about the relative causes and effects in the relationship between EphA2 expression and p53 status. While much previous investigation suggests that p53 regulates EphA2 expression, it cannot be excluded that EphA2 overexpression might alter p53 status.…”