Regulation of SV40 large T-antigen stability by reversible acetylation

Shimazu, Tadahiro; Komatsu, Yasuhiko; Nakayama, Keiko; Fukazawa, Hidesuke; Horinouchi, Sueharu; Yoshida, Minoru

doi:10.1038/sj.onc.1209731

Cited by 42 publications

(40 citation statements)

References 40 publications

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“…44 This implies that, in the presence of p53, some of the potential transforming properties of large T are inhibited or diminished, as was shown in a mouse model of pancreatic islet carcinogenesis. 38,45 Together with the existing communication and coordination between the p53 and Akt pathways, it is very well possible that the mechanisms of malignant transformation by SV40 T antigen and TCL1 are related. Compared with the E-TCL1 mice, in which V H regions of leukemias consistently differed only marginally (Ͻ 2.0%) from the germline, our IgH.TE/IgH.T mouse models are unique in that, next to leukemias with unmutated BCR, we also observed leukemias with extensive SHM (Table 1).…”

Section: Discussionmentioning

confidence: 99%

A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen

Brugge¹,

Bruijn

et al. 2009

Blood

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IntroductionB-cell chronic lymphocytic leukemia (B-CLL), 1,2 the most common leukemia in the Western world, is characterized by the accumulation of a monoclonal population of mature B cells that aberrantly express CD5. 3,4 The clinical course of CLL is extremely heterogeneous: whereas some patients survive more than a decade with stable disease, others die of the disease within months despite aggressive treatment. This heterogeneity is associated with variability in the expression pattern of a number of different proteins, and also with the presence of different chromosomal aberrations. 5 Approximately half of the CLL cases have 13q14deletions, apparently involving the linked microRNA molecules miR15 and miR16, which are thought to be negative regulators of the antiapoptotic gene Bcl2. 2 Deletions on chromosome 17p, affecting the p53 protein, are less frequent and are associated with poor prognosis. 6,7 CLLs manifest a unique gene-expression signature that differs from other lymphoid cancers, suggesting a common mechanism of transformation or a homogeneous cell population of origin. 2 CLL has been subdivided into 2 prognostic subsets, based on the presence of somatic mutations of the immunoglobulin (Ig) heavy (H) chain variable (V H ) genes. A total of 50% to 70% of CLL patients have mutated V H genes, probably reflecting antigen-driven postgerminal center (GC) selection, and have a more favorable prognosis than those with unmutated B-cell receptors. CLL Ig V H regions also exhibit unique complementarity determining region 3 (CDR3) features that characterize and differentiate aggressive unmutated from more indolent mutated CLLs. In particular, unmutated poor outcome cases frequently contain long CDR3s with amino acid residues that favor polyreactivity. Interestingly, both unmutated and mutated CLLs are thought to derive from self-reactive B-cell precursors. 8 In this context, it has been found that approximately 3% to 4% of healthy persons older than 40 years of age have a population of monoclonal lymphocytes in their blood with immunophenotypic characteristics of CLL cells. 2 The simian virus 40 (SV40) T antigen is a potent oncogene able to transform many cell types 9,10 and has been implicated in the etiology of various cancers. 11,12 The SV40 T antigen has transforming activity by inactivating p53 and Rb proteins and inducing genomic instability. 13 Several studies point to a causative role of SV40 in the formation of human B-cell malignancies, including non-Hodgkin lymphoma. [14][15][16] Transgenic expression of the SV40 T gene under the control of the IgH enhancer induced hyperproliferation of multilineage hematopoiesis, reminiscent of myelodysplastic syndromes in humans. 17 In this report, we aimed to accomplish sporadic SV40 T gene expression in the B-cell lineage in mice. We introduced the SV40 T gene, without its promoter and in opposite transcriptional orientation between the IgH chain D and J H segments. As antisense transcription takes place across the D-J H region in pro-B cells, 18 it is possible t...

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Section: Discussionmentioning

confidence: 99%

A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen

Brugge¹,

Bruijn

et al. 2009

Blood

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“…In addition to these shared properties, differences in replication between viruses have been reported to occur because of structural variation between viral core origins and TAg pro-teins (4,5,47,51,52); differences in TAg acetylation that either stimulate replication (109), or regulate TAg stability (73,84); selective interactions with the host p180 DNA Pol ␣-primase and p48 primase subunits (9,94) and with RPA (103); steps in replication beyond initiation (89); and modulation of replication by 5Ј and 3Ј cis-acting origin proximal sequences that alter activities of replication proteins and determine chromatin structure and intranuclear DNA localization (14,29,63,91,100,104,106,109). Such virus-and host-specific features may affect the outcomes of viral infection.…”

mentioning

confidence: 99%

Restriction of Human Polyomavirus BK Virus DNA Replication in Murine Cells and Extracts

Mahon

Liang

Tikhanovich

et al. 2009

J Virol

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“…6D), based on counting colonies of five independent fields by inverted microscopy (three independent soft agar plates) with discrimination between large (Ø, Ն150 m), medium (Ø, 50 to 150 m), and small (Ø, Յ50 m) colonies and calculating the number of colonies, up to the complete dish. (82). However, we observed similar levels of LT in 3T3 LT and in 10-1 LT cells (Fig.…”

Section: Discussionmentioning

confidence: 49%

Wild-Type p53 Enhances Efficiency of Simian Virus 40 Large-T-Antigen-Induced Cellular Transformation

Hermannstädter

Ziegler

Kühl

et al. 2009

J Virol

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The tumor suppressor p53 was discovered in 1979 as a cellular protein complexed to the simian virus 40 (SV40) large tumor antigen (LT) (49, 52). Based on the seeming analogy to the complex of the polyoma virus middle T-antigen with the cellular Src protein (12, 13), p53 initially was considered a cellular oncoprotein recruited by LT. This assumption was further supported by experiments demonstrating that p53 was able to immortalize certain primary cells and to cooperate with activated Ras in cellular transformation (27,65,72). However, these initial experiments had been performed with mutant p53 genes, and in 1989 the true nature of p53 as a tumor suppressor was established (31, 42). The discovery of p53 as a tumor suppressor not only spurred research on the role of p53 in tumorigenesis but also led to a renaissance of DNA tumor virus research, as the transforming proteins of polyoma-, papilloma-, and adenoviruses all target the tumor suppressor proteins p53 and pRb (16,22,39,50,53,64,92). Consistent with the functional inactivation of p53 in human and animal tumors, a wealth of evidence demonstrated that the interaction of transforming proteins with p53 also inactivated p53 function.Cellular transformation by SV40 differs from cellular transformation by most other DNA tumor viruses insofar as SV40 LT, the major transforming protein of SV40, is able to perform both major steps of cellular transformation in vitro, immortalization and phenotypic transformation, by itself, while other DNA tumor viruses require the cooperation of at least two viral transforming proteins (11,23,44,48). For example, immortalization of primary cells by the E1A protein of adenovirus or the E7 protein of human papilloma viruses (18,69) requires the functional elimination of the proapoptotic, senescence-inducing functions of p53 by other viral proteins that inactivate p53 (e.g., its sequestration, degradation by the E1B 55K and E4orf6 proteins of adenovirus, or its degradation by the E6 protein of human papillomaviruses) (36,68,77,85,97). Thus, while it is undisputed that SV40 LT eliminates p53 tumor suppressor functions during cellular immortalization, the role of the LT-p53 complex in phenotypic transformation seems to be more complex (33,61). In this respect, our laboratory already in 1987 provided evidence that metabolic stabilization of p53 is not simply a consequence of its physical interaction with LT (19,20) but is an active cellular process that correlates with cellular transformation (21, 87-89, 94, 96). The finding raised the question of why the p53 protein, when destined to be functionally eliminated, should be stabilized during cellular transformation. Also, animal experiments revealed that SV40 is more efficient in promoting tumor growth when wt p53 is present (41). The suggestion that p53 in complex with SV40 LT might support SV40 phenotypic transformation has been received with due skepticism. However, recently it has been reported that human papillomavirus type 16 E6 protein mediated degradation of p53 in SV40-transformed...

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Regulation of SV40 large T-antigen stability by reversible acetylation

Cited by 42 publications

References 40 publications

A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen

A mouse model for chronic lymphocytic leukemia based on expression of the SV40 large T antigen

Restriction of Human Polyomavirus BK Virus DNA Replication in Murine Cells and Extracts

Wild-Type p53 Enhances Efficiency of Simian Virus 40 Large-T-Antigen-Induced Cellular Transformation

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