Human herpesvirus 6 (HHV-6) ORF-1 transactivating gene exhibits malignant transforming activity and its protein binds to p53

Kashanchi, Fatah; Araujo, John C.; Doniger, Jay; Muralidhar, Sumitra; Hoch, Renée V.; Khleif, Samir N.; Mendelson, Elliot; Thompson, Jerry T.; Azumi, Norio; Brady, John; Luppi, Mario; Torelli, Giuseppe; Rosenthal, Leonard J.

doi:10.1038/sj.onc.1200840

Cited by 81 publications

(65 citation statements)

References 34 publications

(41 reference statements)

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“…The closely related virus HHV-6A encodes a protein, DR7, that, when injected into nude mice, causes fibrosarcoma. The DR7 protein can bind directly to p53 and abolish p53-activated transcription (Kashanchi et al, 1997). In addition, DNA from HHV-6B, in particular, but also from HHV-6A, has been detected in Hodgkin's lymphoma and oral carcinoma (Braun et al, 1997;Kashanchi et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Human cytomegalovirus (HCMV) (Speir et al, 1994;Muralidhar et al, 1996;Tsai et al, 1996;Bonin & McDougall, 1997;Castillo et al, 2005) and possibly HHV-6A (Kashanchi et al, 1997;Takemoto et al, 2005) and HHV-6B (De Bolle et al, 2004;Takemoto et al, 2004;Øster et al, 2005) interfere with the tumour suppressor protein p53. The major functions of p53 are associated with maintaining the integrity of the genome by inducing cell-cycle arrest, senescence or apoptosis (Jin & Levine, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

Øster

Bundgaard

Hupp

et al. 2008

Journal of General Virology

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Here, we demonstrate that human herpesvirus 6B (HHV-6B) infection upregulates the tumour suppressor p53 and induces phosphorylation of p53 at Ser392. Interestingly, phosphorylation at the equivalent site has previously been shown to correlate with p53 tumour suppression in murine models. Although the signalling pathways leading to Ser392 phosphorylation are poorly understood, they seem to include casein kinase 2 (CK2), double-stranded RNA-activated protein kinase (PKR), p38 or cyclin-dependent kinase 9 (Cdk9). By using column chromatography and in vitro kinase assays, CK2 and p38, but not PKR or Cdk9, eluted in column fractions that phosphorylated p53 at Ser392. However, treatment of cells with neither the CK2 and Cdk9 inhibitor 5,6-dichloro-1-β-d-ribofuranosylbenzimidazole (DRB) nor p38 kinase inhibitors reduced HHV-6B-induced Ser392 phosphorylation significantly. Knockdown of the CK2β subunit or p38α by small interfering RNA had no effect on HHV-6B-induced phosphorylation of p53 at Ser392. Thus, HHV-6B induces p53 Ser392 phosphorylation by an atypical pathway independent of CK2 and p38 kinases, whereas mitogen-activated protein (MAP) kinase signalling pathways are involved in viral replication.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

Øster

Bundgaard

Hupp

et al. 2008

Journal of General Virology

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“…Relevant to this, we recently identified the first HHV-6 protein, called ORF-1, which has a transactivating and transforming activity mediated through the binding to p53. 20 As we already detected the sequences encoding for ORF-1 in HD tissues in vivo, 20 we are currently looking for the expression of this oncoprotein in R-S and Hodgkin cells. Furthermore, similarly to what occurs in AILD, HHV-6 infection of HD tissues is mainly a latent infection, and the expression of viral antigens indicative of a replicative cycle was limited to a small number of cells and restricted to few cell types, including plasma cells.…”

Section: Discussionmentioning

confidence: 99%

“…[17][18][19] The first specific oncoprotein of HHV-6, called ORF-1, has also been recently identified. 20 Furthermore, since its first isolation from the peripheral blood of patients with lymphomas, 21 serological 22,23 and molecular 22,24 -27 studies have suggested an association between HHV-6 infection and lymphoproliferative diseases.…”

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confidence: 99%

Expression of Human Herpesvirus-6 Antigens in Benign and Malignant Lymphoproliferative Diseases

Luppi

Barozzi

Garber

et al. 1998

The American Journal of Pathology

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145

110

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Immunohistochemistry was used to look for the expression of human herpesvirus-6 (HHV-6) antigens in a well characterized series of benign , atypical, and malignant lymphoid lesions , which tested positive for the presence of HHV-6 DNA. A panel of specific antibodies against HHV-6 antigens , characteristic either of the early (p41) or late (p101K , gp106, and gp116) phases of the viral cycle , was applied to the lymphoid tissues from 15 non-Hodgkin's lymphomas , 14 Hodgkin's disease cases , 5 angioimmunoblastic lymphadenopathies with dysproteinemia , 14 reactive lymphadenopathies , and 2 cases of sinus histiocytosis with massive lymphadenopathy (RosaiDorfman disease). In lymphomatous tissues , the expression of late antigens was documented only in reactive cells , and mainly in plasma cells. Of interest, the expression of the early p41 antigen was detected in the so-called "mummified" Reed-Sternberg cells, in two Hodgkin's disease cases. In reactive lymphadenopathies , the HHV-6 late antigen-expressing cells were plasma cells , histiocytes , and rare granulocytes distributed in interfollicular areas. In both cases of Rosai-Dorfman disease , the p101K showed an intense staining in follicular dendritic cells of germinal centers , whereas the gp106 exhibited an intense cytoplasmic reaction in the abnormal histiocytes , which represent the histological hallmark of the disease.

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“…Such abrogation of some or all of normal tumor suppressor activity of p53 may be responsible, at least in part, for their malignant phenotype of NIH3T3/mot-2 cells. Recently, inactivation of p53 by HHV-6 has been reported to result in malignant transformation of NIH 3T3 cells [25]. Furthermore, RS-4 cells that have a higher expression level of mot-2 than NIH 3T3 cells and possess mutant p53 do not show malignant phenotype (unpublished observations) suggesting that the transforming activity of mot-2 may be mediated mostly by inactivation of wild type p53.…”

Section: Resultsmentioning

confidence: 91%

NIH 3T3 cells malignantly transformed by mot-2 show inactivation and cytoplasmic sequestration of the p53 protein

Wadhwa¹,

Takano

Mitsui

et al. 1999

Cell Res

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In previous studies we have reported that a high level of expression of mot-2 protein results in malignant transformation of NIH 3T3 cells as analyzed by anchorage independent growth and nude mice assays [Kaul et al., Oncogene, 17, 907-11, 1998]. Mot-2 was found to interact with tumor suppressor protein p53. The transient overexpression of mot-2 was inhibitory to transcriptional activation function of p53 [Wadhwa et al., J. Biol. Chem., 273, 29586-91, 1998]. We demonstrate here that mot-2 transfected stable clone of NIH 3T3 that showed malignant properties indeed show inactivation of p53 function as assayed by exogenous p53 dependent reporter. The expression level of p53 in response to UV-irradiation was lower in NIH 3T3/mot-2 as compared to NIH 3T3 cells and also exhibited delay in reaching peak. Furthermore, upon serum starvation p53 was seen to translocate to the nucleus in NIH 3T3, but not in its mot-2 derivative. The data suggests that mot-2 mediated cytoplasmic sequestration and inactivation of p53 may operate, at least in part, for malignant phenotype of NIH 3T3/ mot-2 cells.

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Human herpesvirus 6 (HHV-6) ORF-1 transactivating gene exhibits malignant transforming activity and its protein binds to p53

Cited by 81 publications

References 34 publications

Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway

Expression of Human Herpesvirus-6 Antigens in Benign and Malignant Lymphoproliferative Diseases

NIH 3T3 cells malignantly transformed by mot-2 show inactivation and cytoplasmic sequestration of the p53 protein

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