The SV40 Large T Antigen-p53 Complexes Bind and Activate the Insulin-like Growth Factor-I Promoter Stimulating Cell Growth

Bocchetta, Maurizio; Eliasz, Sandra; Marco, Melissa A. De; Rudzinski, Jennifer; Zhang, Lei; Carbone, Michele

doi:10.1158/0008-5472.can-07-5203

Cited by 80 publications

(63 citation statements)

References 18 publications

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“…These observations suggest that SV40 large T plays an essential role in reprogramming sheep somatic cells. SV40 large T is an essential protein for SV40 DNA replication and disables the retinoblastoma and p53 tumor suppressor pathways [31][32][33][34]. It has been reported that knocking down p53 greatly increases reprogramming efficiency [35][36][37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Reprogramming of ovine adult fibroblasts to pluripotency via drug-inducible expression of defined factors

et al. 2011

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Reprogramming of somatic cells in the enucleated egg made Dolly, the sheep, the first successfully cloned mammal in 1996. However, the mechanism of sheep somatic cell reprogramming has not yet been addressed. Moreover, sheep embryonic stem (ES) cells are still not available, which limits the generation of precise gene-modified sheep. In this study, we report that sheep somatic cells can be directly reprogrammed to induced pluripotent stem (iPS) cells using defined factors (Oct4, Sox2, c-Myc, Klf4, Nanog, Lin28, SV40 large T and hTERT). Our observations indicated that somatic cells from sheep are more difficult to reprogram than somatic cells from other species, in which iPS cells have been reported. We demonstrated that sheep iPS cells express ES cell markers, including alkaline phosphatase, Oct4, Nanog, Sox2, Rex1, stage-specific embryonic antigen-1, TRA-1-60, TRA-1-81 and E-cadherin. Sheep iPS cells exhibited normal karyotypes and were able to differentiate into all three germ layers both in vitro and in teratomas. Our study may help to reveal the mechanism of somatic cell reprogramming in sheep and provide a platform to explore the culture conditions for sheep ES cells. Moreover, sheep iPS cells may be directly used to generate precise gene-modified sheep.

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Section: Discussionmentioning

confidence: 99%

Reprogramming of ovine adult fibroblasts to pluripotency via drug-inducible expression of defined factors

et al. 2011

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“…The literature also suggests that p53 stabilization may play a role in naturally occurring p53 gain-of-function mutants that exhibit an enhanced transformation potential (62), and it is tantalizing to think that LT might make use of a p53 gain-offunction in transformation (6,19,20). Thus, the interaction of LT with Bub1 might contribute to transformation both in an acute fashion via p53 stabilization and via a long-term effect on chromosome stability.…”

Section: Discussionmentioning

confidence: 99%

Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

Hein

Boichuk

et al. 2009

J Virol

119

132

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Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shownto lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of ␥-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.Simian virus 40 (SV40) is a small DNA tumor virus, belonging to the polyomavirus family, that induces a productive infection in its natural host, the rhesus macaque, but yields oncogenic transformation in nonpermissive hosts such as rodent cells. The highly multifunctional large T antigen (LT) is the key early protein essential for both driving viral replication as well as inducing cellular transformation. Two other early proteins, small t antigen and 17k T antigen (17k) may perform auxiliary functions during the viral life cycle (39, 69). LT has served as a powerful model system for understanding fundamental cellular processes such as nuclear translocation, transcriptional regulation, eukaryotic DNA replication, immortalization, and malignant transformation (reviewed in references 26 and 37).LT overrides cellular control mechanisms and reprograms the host cell to create a permissive environment for viral replication. The deregulation of cellular proliferation is dependent on LT's interaction with specific host proteins, among which the tumor suppressors p53 and the retinoblastoma protein (pRB) are the best characterized (reviewed in reference 37). Transformation in vitro and tumor induction in vivo frequently depend on LT binding and functionally inactivating these key tumor suppressors (37).

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“…Thus, in contrast to p53 target genes, possible LT target genes in cellular transformation cannot be detected by sequence homology of possible LT response elements. Recently, however, Bocchetta et al (6) demonstrated that the IGF1 gene is a direct transcriptional target of the LT-p53 complex, which positively regulates IGF1 transcription in SV40-transformed human mesothelial cells. Our analyses of Igf1 gene activity in SV40-transformed mouse fibroblasts contradict this result.…”

Section: Discussionmentioning

confidence: 99%

“…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 human mesothelial cells induces a growth arrest by abrogating insulin-like growth factor 1 (IGF1) signaling (6). Those authors reported that LT and p53 associate with the IGF1 promoter within a multiprotein complex, in which p300 might be an important component required for IGF1 transcription.…”

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confidence: 99%

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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The SV40 Large T Antigen-p53 Complexes Bind and Activate the Insulin-like Growth Factor-I Promoter Stimulating Cell Growth

Abstract: Inactivation of cellular p53 is a crucial step in carcinogenesis.

Cited by 80 publications

References 18 publications

Reprogramming of ovine adult fibroblasts to pluripotency via drug-inducible expression of defined factors

Reprogramming of ovine adult fibroblasts to pluripotency via drug-inducible expression of defined factors

Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

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

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