The SV40 large T oncoprotein disrupts DNA-binding of the cell cycle-regulated transcriptional repressor CDF

Zwicker, Jörk; Körner, K.; Müller, Rolf

doi:10.1038/sj.onc.1202063

Cited by 6 publications

(5 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A link between p53 and CDF-1 is further supported by the recent observation that simian virus 40 large T antigen, which binds and inactivates p53, prevents CDF-1 from binding to CDE elements in WI-38 cells (63). Further components of this pathway and its role in DNA damage-induced G 2 /M arrest are unknown at present, but it is interesting to speculate on these (Fig.…”

Section: Discussionmentioning

confidence: 68%

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G₂/M Arrest in Human Cells

Badie

Itzhaki²,

Sullivan

et al. 2000

Molecular and Cellular Biology

View full text Add to dashboard Cite

Entry into mitosis is controlled by the cyclin-dependent kinase CDK1 and can be delayed in response to DNA damage. In some systems, such G 2 /M arrest has been shown to reflect the stabilization of inhibitory phosphorylation sites on CDK1. In human cells, full G 2 arrest appears to involve additional mechanisms. We describe here the prolonged (>6 day) downregulation of CDK1 protein and mRNA levels following DNA damage in human cells. This silencing of gene expression is observed in primary human fibroblasts and in two cell lines with functional p53 but not in HeLa cells, where p53 is inactive. Silencing is accompanied by the accumulation of cells in G 2 , when CDK1 expression is normally maximal. The response is impaired by mutations in cis-acting elements (CDE and CHR) in the CDK1 promoter, indicating that silencing occurs at the transcriptional level. These elements have previously been implicated in the repression of transcription during G 1 that is normally lifted as cells progress into S and G 2 . Interestingly, we find that other genes, including those for CDC25C, cyclin A2, cyclin B1, CENP-A, and topoisomerase II␣, that are normally expressed preferentially in G 2 and whose promoter regions include putative CDE and CHR elements are also downregulated in response to DNA damage. These data, together with those of other groups, support the existence of a p53-dependent, DNA damage-activated pathway leading to CHR-and CDE-mediated transcriptional repression of various G 2 -specific genes. This pathway may be required for sustained periods of G 2 arrest following DNA damage.

show abstract

Section: Discussionmentioning

confidence: 68%

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G₂/M Arrest in Human Cells

Badie

Itzhaki²,

Sullivan

et al. 2000

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…1). This was surprising, since ORC1 is E2F‐regulated, and SV40 transformation is known to deregulate such genes [Nevins, 1992; Zwicker et al, 1999], whereas ORC2 and ORC4 are not E2F‐regulated [Ohtani et al, 1996; Springer et al, 1999]. On the other hand, HeLa cells harbor significantly more ORC1 than the SV40‐transformed primary cells, but the levels of ORC2 and ORC4 are similar between these lines.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of ORC subunits and increased ORC‐chromatin association in transformed mammalian cells

McNairn

Gilbert

2005

J of Cellular Biochemistry

View full text Add to dashboard Cite

The origin recognition complex (ORC) is a conserved heterohexamer required for the formation of pre-replication (pre-RC) complexes at origins of DNA replication. Many studies of ORC subunits have been carried out in transformed human cell lines but the properties of ORC in primary cells have not been addressed. Here, we compare the expression levels and chromatin-association of ORC subunits in HeLa cells to the primary human cell line, WI38, and a virally transformed derivative of WI38, VA13. ORC subunits 2 and 4 were highly overexpressed in both HeLa and VA13, whereas ORC1 levels were elevated in VA13 but considerably higher in HeLa cells. Cellular extraction revealed that the proportion of ORC2 and ORC4 subunits bound to chromatin was similar in all three cell lines throughout the cell-cycle. In contrast, very little ORC1 was associated with chromatin after extraction of primary WI38 cells, whereas the majority of overexpressed ORC1 in both HeLa and VA13 co-fractionated with chromatin throughout the cell-cycle. Although none of the cell lines displayed significant changes in the levels or chromatin-association of ORC during the cell-cycle, the chromatin-associated fraction of ORC1 displayed an increase in apparent molecular weight during S-phase. Similar experiments comparing immortalized CHO cells to an isogenic virally transformed derivative revealed no changes in levels of ORC subunits but an increase in the proportion of all three ORC subunits associated with chromatin. These results demonstrate a complex influence of cellular immortalization and transformation properties on the expression and regulation of ORC subunits. These results extend the potential link between cancer and deregulation of pre-RC proteins, and underscore the importance of considering the transformation status of cell lines when working with these proteins.

show abstract

“…This indicates that EMSAs do not necessarily reveal the actual changes occurring at this site. The same may hold true for the effects of the T antigens because it was shown by in vivo footprinting of another promoter carrying a CDE-CHR, that of the cdc25C gene, that proteins binding to the CDE-CHR are removed by SV40 T antigen (46). Since different promoters which all carry CDE-CHR motifs are activated at different times during the cell cycle and are therefore probably not regulated in exactly the same way, it would be interesting to see, using in vivo footprinting, whether Py T antigens can change protein binding to the CDE-CHR of the cyclin A promoter.…”

Section: Discussionmentioning

confidence: 99%

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

Schüchner

Nemethova

Belisova

et al. 2001

J Virol

View full text Add to dashboard Cite

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 ...

show abstract

The SV40 large T oncoprotein disrupts DNA-binding of the cell cycle-regulated transcriptional repressor CDF

Cited by 6 publications

References 16 publications

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G₂/M Arrest in Human Cells

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G₂/M Arrest in Human Cells

Overexpression of ORC subunits and increased ORC‐chromatin association in transformed mammalian cells

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

Contact Info

Product

Resources

About

The SV40 large T oncoprotein disrupts DNA-binding of the cell cycle-regulated transcriptional repressor CDF

Cited by 6 publications

References 16 publications

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G2/M Arrest in Human Cells

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G2/M Arrest in Human Cells

Overexpression of ORC subunits and increased ORC‐chromatin association in transformed mammalian cells

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

Contact Info

Product

Resources

About

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G₂/M Arrest in Human Cells

Repression of CDK1 and Other Genes with CDE and CHR Promoter Elements during DNA Damage-Induced G₂/M Arrest in Human Cells