E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis

Polager, Shirley; Kalma, Yael; Berkovich, Eli; Ginsberg, Doron

doi:10.1038/sj.onc.1205102

Cited by 246 publications

(215 citation statements)

References 45 publications

(45 reference statements)

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“…In synchronised murine cells, TS mRNA and TS activity increased as cells reach S-phase (Navalgund et al, 1980;Nagarajan and Johnson, 1989). Ectopic over-expression of E2F transcription factors leads to upregulation of TS transcripts (Ishida et al, 2001;Kalma et al, 2001;Polager et al, 2002). Since E2F transcription factors are one of the main effectors of the G 1 /S transition (Fan and Bertino, 1997) that control the expression of a number of genes required for DNA synthesis (DeGregori et al, 1995), these studies reinforced the hypothesis that TS is a S-phasedependent enzyme.…”

Section: Discussionmentioning

confidence: 83%

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Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

2007

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Thymidylate synthase (TS) is the enzyme that catalyses the last step in de novo thymidylate synthesis. It is of interest clinically because it is an effective target for drugs such as 5-fluorouracil, often used in combination therapy. Despite a number of earlier reports indicating that TS is a cell cycle-dependent enzyme, this remains equivocal. Here, we show that in HCT116 cells synchronised by serum starvation, there is a clear dissociation between the expression of cyclin E (a well-characterised cell-cycle protein) and TS. Although both cyclin E and TS mRNA and protein increased during G 1 , TS upregulation was delayed. Moreover, TS levels did not decrease following S-phase completion while cyclin E decreased sharply. Similarly, clear differences were seen between cyclin E and TS as asynchronously growing HCT116 cells were growth-inhibited by low-serum treatment. In contrast to previous reports using rodent cells, adenovirus-mediated over-expression of E2F1 and cyclin E in three human cell lines had no effect on TS. Cell-cycle progression was blocked by treatment of cells with pharmacological inhibitors of CDK2 and CDK4 and by ectopic expression of p16INK4A. Whereas CDK2 inhibition had no effect on TS levels, inhibition of CDK4 was associated with decreased TS protein levels. These results provide the first evidence that drugs targeting CDK4 may be useful with anti-TS drugs as combination therapy for cancer.

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Section: Discussionmentioning

confidence: 83%

“…In rodent cells, microarray analysis has shown that ectopic expression of various E2F family members increase TS mRNA levels (Ishida et al, 2001;Kalma et al, 2001;Polager et al, 2002). In human cells, two E2F consensus binding sites are found in the inverted repeat of the TS promoter.…”

mentioning

confidence: 99%

Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

2007

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“…These cell cycle effects are likely due to the ability of RBF and dE2F1 to control the expression of targets such as cyclin E and string (Drosophila cdc25), as well as multiple DNA replication factors that regulate the progression of different cell cycle phases. Recent screens of Rb/E2F target genes by microarray have also identified cell cycle checkpoint genes (Polager et al, 2002;Ren et al, 2002). For example, Mad2, a spindle checkpoint gene, was recently identified as an E2F target.…”

Section: Cell Cycle Roles Of the Rb Family Of Proteinsmentioning

confidence: 99%

“…Several different approaches have been carried out. Initial microarray screens focused on the overexpression of E2F or Rb family members (Muller et al, 2001;Polager et al, 2002). While these studies identified large arrays of altered genes, they cannot distinguish genes directly regulated by Rb or E2F from genes that changed expression due to secondary effects of Rb or E2F expression (such as alterations in the cell cycle).…”

Section: Transcriptional Targets Of Rb and E2f Proteinsmentioning

confidence: 99%

Retinoblastoma family genes

2006

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“…In addition, recent efforts to explore downstream effectors of mammalian E2F using DNA microarrays and chromatin immunoprecipitation (ChIP) have identified a variety of putative E2F target genes. These targets are thought to be involved not only in cell cycle progression but also in apoptosis, checkpoints, DNA repair, metabolism, development and differentiation (Ishida et al, 2001;Muller et al, 2001;Polager et al, 2002;Ren et al, 2002;Weinmann et al, 2002;Cam et al, 2004). However, the exact roles and regulatory mechanisms of E2F in biological processes other than cell cycle progression are yet to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Identification of novel E2F1 target genes regulated in cell cycle-dependent and independent manners

et al. 2005

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The transcription factor E2F mediates cell cycle-dependent expression of genes important for cell proliferation in response to growth stimulation. To further understand the role of E2F, we utilized a sensitive subtraction method to explore new E2F1 targets, which are expressed at low levels and might have been unrecognized in previous studies. We identified 33 new E2F1-inducible genes, including checkpoint genes Claspin and Rad51ap1, and four genes with unknown function required for cell cycle progression. Moreover, we found three groups of E2F1-inducible genes that were not induced by growth stimulation. At least, two groups of genes were directly induced by E2F1, indicating that E2F1 can regulate expression of genes not induced during the cell cycle. One included Neogenin, WASF1 and SGEF genes, which may have a role in differentiation or development. The other was the cyclin-dependent kinase inhibitor p27 Kip1 , which was involved in suppression of inappropriate cell cycle progression induced by deregulated E2F. E2F1-responsive regions of these genes were located more upstream than those of typical E2F targets and did not have typical E2F sites. These results indicate that there are groups of E2F1 targets, which are regulated in a distinct manner from that of typical E2F targets.

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E2Fs up-regulate expression of genes involved in DNA replication, DNA repair and mitosis

Cited by 246 publications

References 45 publications

Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

Expression of thymidylate synthase in human cells is an early G1 event regulated by CDK4 and p16INK4A but not E2F

Retinoblastoma family genes

Identification of novel E2F1 target genes regulated in cell cycle-dependent and independent manners

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