Expression of p53 and human herpesvirus-8 (HHV-8)-encoded latency-associated nuclear antigen with inhibition of apoptosis in HHV-8-associated malignancies

Katano, Harutaka; Sato, Yuko; Sata, Tetsutaro

doi:10.1002/1097-0142(20011215)92:12<3076::aid-cncr10117>3.0.co;2-d

Cited by 75 publications

(59 citation statements)

References 70 publications

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“…In accordance with previous reports, 17 BCBL-1 was found to harbor a heterozygous M246I mutation of TP53. BCP-1 contained two missense mutations leading to single nucleotide changes (M246V and D259N) in both alleles of exon 7.…”

Section: Resultssupporting

confidence: 92%

Mutational analysis of TP53, PTEN, PIK3CA and CTNNB1/ -catenin genes in human herpesvirus 8-associated primary effusion lymphoma

Boulanger¹,

Marchio²,

Hong³

et al. 2009

Haematologica

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Section: Resultssupporting

confidence: 92%

Mutational analysis of TP53, PTEN, PIK3CA and CTNNB1/ -catenin genes in human herpesvirus 8-associated primary effusion lymphoma

Boulanger¹,

Marchio²,

Hong³

et al. 2009

Haematologica

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“…Although p53 mutations occur rarely in KS or PELs (25), our results demonstrate that inactivation of p53-mediated processes occurred through binding of the viral protein LANA to the p53-MDM2 complex in these lymphomas. Nutlin-3a treatment resulted in disruption of interactions among all 3 proteins in this complex and induced cytotoxicity at concentrations that were nonapoptotic in EBV-transformed LCLs, which express WT p53.…”

Section: Discussionmentioning

confidence: 67%

“…Interestingly, BCBL-1 cells have previously been shown to harbor a TP53 missense mutation (M246I; ref. 25) in one copy of the TP53 gene (29), providing a possible explanation for the attenuated response. Interestingly, PEL cells express relatively high levels of p53 binding protein 1 (53BP1), a component of the ataxia telangiectasia mutated-checkpoint kinase 2 (ATM-Chk2) DNA damage checkpoint pathway (30, 31) recently identified as a critical mediator of cellular cytotoxicity by Nutlin-3a (27).…”

Section: Nutlin-3a Stabilizes P53 and Activates The P53 Pathway In Pementioning

confidence: 99%

“…Despite some interesting new therapeutic leads such as inhibition of NF-κB signaling (18,19) or RNA interference against viral latent proteins (20), the current clinical treatments based on high-dose chemotherapy regimens are neither potent nor selective for this cancer (21,22), and PEL remains a fatal disease. Although p53 mutations are relatively common in hematopoietic malignancies, the majority of the PELs appear to have WT p53 (23)(24)(25), suggesting that genetic alterations in the p53 gene are not selected for during PEL tumorigenesis. However, the pathogenetic mechanisms leading to lymphomas by this oncogenic tumor virus are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas

Sarek¹,

Kurki²,

Enbäck³

et al. 2007

J. Clin. Invest.

132

135

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Kaposi's sarcoma herpesvirus (KSHV) is the etiologic agent for primary effusion lymphoma (PEL), a nonHodgkin type lymphoma manifesting as an effusion malignancy in the affected individual. Although KSHV has been recognized as a tumor virus for over a decade, the pathways for its tumorigenic conversion are incompletely understood, which has greatly hampered the development of efficient therapies for KSHV-induced malignancies like PEL and Kaposi's sarcoma. There are no current therapies effective against the aggressive, KSHV-induced PEL. Here we demonstrate that activation of the p53 pathway using murine double minute 2 (MDM2) inhibitor Nutlin-3a conveyed specific and highly potent activation of PEL cell killing. Our results demonstrated that the KSHV latency-associated nuclear antigen (LANA) bound to both p53 and MDM2 and that the MDM2 inhibitor Nutlin-3a disrupted the p53-MDM2-LANA complex and selectively induced massive apoptosis in PEL cells. Together with our results indicating that KSHV-infection activated DNA damage signaling, these findings contribute to the specificity of the cytotoxic effects of Nutlin-3a in KSHV-infected cells. Moreover, we showed that Nutlin-3a had striking antitumor activity in vivo in a mouse xenograft model. Our results therefore present new options for exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment modality for this virally induced lymphoma.

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“…In this context, it is interesting to note that two latent proteins that are tightly coexpressed with K cyclin, LANA and v-FLIP, respectively compromise activation of p53 (63) and promote tumorigenesis by inhibiting lymphocyte apoptosis (64). In addition, KSHV-associated disorders do not display recurrent p53 mutations (65)(66)(67), and LANA was found to colocalize with p53 in KS samples (66). Together with our findings, this therefore suggests an intriguing interplay between latent viral proteins in promoting survival and proliferation of KSHV-infected cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2004

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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.

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Expression of p53 and human herpesvirus-8 (HHV-8)-encoded latency-associated nuclear antigen with inhibition of apoptosis in HHV-8-associated malignancies

Cited by 75 publications

References 70 publications

Mutational analysis of TP53, PTEN, PIK3CA and CTNNB1/ -catenin genes in human herpesvirus 8-associated primary effusion lymphoma

Mutational analysis of TP53, PTEN, PIK3CA and CTNNB1/ -catenin genes in human herpesvirus 8-associated primary effusion lymphoma

Reactivation of the p53 pathway as a treatment modality for KSHV-induced lymphomas

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

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