Polyomavirus large T antigen-dependent DNA amplification

Stiegler, Peter; Schüchner, Stefan; Lestou, Valia S.; Wintersberger, Erhard

doi:10.1038/sj.onc.1200904

Cited by 8 publications

(5 citation statements)

References 34 publications

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“…Although the CDE sequence resembles a binding motif for E2F, complexes forming at the CDE-CHR were distinctly different from those forming at a genuine E2F site, such as that of the mouse thymidine kinase promoter which was employed for comparison. Use of antibodies indicated that the latter complexes contained E2F4 and p130, in agreement with earlier results in arrested mouse 3T3 cells (37); in contrast, neither antibody provided evidence for an involvement of these proteins in complexes forming on the CDE-CHR. Although this again agrees with published results (14), the possibility cannot be excluded that a much more intricate structure of the protein complexes forming at the CDE-CHR compared with those at an E2F site does not allow sufficient access for antibodies to cause changes in the complex formation or its size (see Discussion).…”

Section: Vol 75 2001supporting

confidence: 78%

Transactivation of Murine Cyclin A by Polyomavirus Large and Small T Antigens

Schüchner

Nemethova

Belisova

et al. 2001

J Virol

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Polyomavirus large and small T antigens cooperate in the induction of S phase in serum-deprived Swiss 3T3 cells. While the large T antigen is able to induce S phase-specific enzymes, we have recently shown that both T antigens contribute to the production of the cyclins E and A and that the small T antigen is essential for the induction of cyclin A-dependent cdk2 activity (S. Schüchner and E. Wintersberger, J. Virol. 73:9266-9273, 1999). Here we present our attempts to elucidate the mechanisms by which the large and the small T antigens transactivate the murine cyclin A gene. Using Swiss 3T3 cells carrying the T antigens and various mutants thereof under the hormone-inducible mouse mammary tumor virus promoter, as well as transient-cotransfection experiments with the T antigens and cyclin A promoter-luciferase reporter constructs, we found the following. The large T antigen activates the cyclin A promoter via two transcription factor binding sites, a cyclic AMP responsive element (CRE), and the major negative regulatory site called CDE-CHR. While an intact binding site for pocket proteins is required for the function of this T antigen at the CDE-CHR, its activity at the CRE is largely independent thereof. In contrast, an intact J domain and an intact zinc finger are required at both sites. The small T antigen also appears to have an influence on the cyclin A promoter through the CRE as well as the CDE-CHR. For this an interaction with protein phosphatase 2A is essential; mutation of the J domain does not totally eliminate but greatly reduces the transactivating ability.The induction of S phase of the cell cycle is a complex reaction usually initiated at the cell surface through binding of ligands to receptors. Signal transduction pathways lead to the synthesis of S phase-specific enzymes and regulators, including the cyclins E and A. DNA tumor viruses require cells in S phase because they heavily depend on the cellular DNA synthesis machinery for the replication of their own DNA. Since they frequently infect differentiated cells, they have to interfere with the cellular mechanisms of growth regulation in order to drive cells out of the G 0 phase and into the S phase (reviewed in reference 19). This is accomplished by viral proteins which interact with various intermediates of the signal transduction pathway downstream of events taking place at the cell surface. One class of target for such viral proteins are the pocket proteins: pRB and its relatives p107 and p130. They negatively regulate members of the transcription factor family E2F (reviewed in reference 8). Adenovirus E1A, human papillomavirus (HPV) E7 protein, and the large T (LT) antigens of simian virus 40 (SV40), and polyomavirus (Py) bind to pocket proteins and cause a dissociation of the repressive complexes, which results in the transactivation of E2F responsive genes (19). Another region of the pleiotropic T antigens which is essential for this reaction is the J domain (reviewed in references 4 and 16), a sequence present in many chaperones capable ...

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Section: Vol 75 2001supporting

confidence: 78%

Transactivation of Murine Cyclin A by Polyomavirus Large and Small T Antigens

Schüchner

Nemethova

Belisova

et al. 2001

J Virol

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“…Although cytochalasin D and blebbistatin cause a relative doubling of chromosome number, the fact that these cells were originally tetraploid might have influenced our observations. Therefore, focus forming assays were repeated in the hyperdiploid cell line REF52 (average of 56 chromosomes/cell) [Stiegler et al, 1997]. REF52 cells behave very similarly to normal fibroblasts in at least two respects: (i) they require a cooperating oncogene to be transformed by Ras, (ii) they are unable to generate resistance to PALA, a feature closely associated with the normal functioning of p53-dependent pathways for growth arrest [Franza et al, 1986;Perry et al, 1992].…”

Section: Polyploidy and Transformation By Rasmentioning

confidence: 99%

Investigating the role of Aurora kinases in RAS signaling

Kosik

Bekier

Katusin

et al. 2008

J of Cellular Biochemistry

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Activating ras mutations are frequently found in malignant tumors of the pancreas, colon, lung and other tissues. RAS activates a number of downstream pathways that ultimately cause cellular transformation. Several recent studies suggested that one of those pathways involves Aurora kinases. Overexpression of Aurora-B kinase can augment transformation by oncogenic RAS, however the mechanism was not determined. The cooperative effect of high levels of Aurora kinase is important since this kinase is frequently overexpressed in human tumors. We have used two Aurora kinase inhibitors to test their effect on RAS signaling. We find that these inhibitors have no effect on the phosphorylation of MEK1/2 or MAPK in response to RAS. Furthermore, inhibiting Aurora kinases in human cancer cells with or without activated RAS did not change the length of the cell cycle nor induce apoptosis suggesting that these kinases do not play a direct role in these key cellular responses to activated RAS. Overexpression of Aurora B can cause cells to become polyploid. Also, inducing polyploidy with cytochalasin D was reported to induce neoplastic transformation, suggesting that Aurora overexpression may cooperate with RAS indirectly by inducing polyploidy. We find that inducing polyploidy with cytochalasin D or blebbistatin does not enhance transformation by oncogenic RAS. Our observations argue against a direct role for Aurora kinases in the RAS-MAPK pathway, and suggest that the polyploid state does not enhance transformation by RAS.

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“…It has been shown that loss, decrease in expression, or mutation of Rb2/p130 can be linked to various carcinomas (Cinti et Rb2/p130 is a member of the ''pocket'' protein family (pRb, p130, p107) of tumor suppressors. The members of the ''pocket '' protein family share a high degree of homology and control cell-cycle progression by binding to various members of the E2F family of transcription factors and histone deacetylase 1 (HDAC1), which enhances transcriptional repression (Paggi et al, 1996;Stiegler et al, 1997;Stiegler et al, 1998;Zhang et al, 2000;Zini et al, 2001;Tonini et al, 2002). During cell-cycle progression, Rb2/p130 becomes hyperphosphorylated by cyclin-dependent kinase (CDK) complexes, which then leads to the ubiquitination and eventual degradation of Rb2/p130 protein by the proteasome.…”

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confidence: 99%

Interaction of PP2A catalytic subunit with Rb2/p130 is required for all‐trans retinoic acid suppression of ovarian carcinoma cell growth

Purev

Giordano

Soprano

et al. 2005

Journal Cellular Physiology

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All-trans retinoic acid (ATRA) treatment causes CAOV3 ovarian carcinoma cells to growth arrest in the G0/G1 phase and to elevate the level of Rb2/p130 protein. PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130, thereby increasing the half-life of Rb2/p130 in the cell. In order to further characterize the interaction between Rb2/p130 and PP2A upon ATRA treatment, we examined the posttranslational modification of PP2A. ATRA treatment leads to hypophosphorylation of PP2A catalytic subunit (PP2Ac) that correlates with increased PP2A activity. In addition, the N-terminus of PP2Ac binds directly to NLS sequences located in the C-terminus of Rb2/p130. Furthermore, CAOV3 cells transfected with a truncated Rb2/p130 construct consisting of only the wt C-terminus grew more aggressively and were less sensitive to ATRA treatment when compared to parental CAOV3 cells. In contrast, CAOV3 cells transfected with a truncated Rb2/p130 construct consisting of only the C-terminus in which the NLS sites were mutated and which could not interact with PP2A, were as sensitive to ATRA treatment as parental CAOV3 cells. These studies suggest that ATRA treatment suppresses the growth of CAOV3 cells via a novel posttranscriptional mechanism involving PP2A.

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Polyomavirus large T antigen-dependent DNA amplification

Cited by 8 publications

References 34 publications

Transactivation of Murine Cyclin A by Polyomavirus Large and Small T Antigens

Transactivation of Murine Cyclin A by Polyomavirus Large and Small T Antigens

Investigating the role of Aurora kinases in RAS signaling

Interaction of PP2A catalytic subunit with Rb2/p130 is required for all‐trans retinoic acid suppression of ovarian carcinoma cell growth

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