Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2

Kalma, Yael; Marash, Lea; Lamed, Yocheved; Ginsberg, Doron

doi:10.1038/sj.onc.1204230

Cited by 66 publications

(54 citation statements)

References 51 publications

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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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“…Semiquantitative RT-PCR was performed essentially as described. 49 Primers specific for GAPDH, 5 0 -ACCACAGTCCATGCCAT CAC and 5 0 -TCCACCACCCTGTTGCTGTA, ASPP1, 5 0 -GAAATGA ACGTCCCATACCC and 5 0 -TTTCAGCAGACAGATTGCC, ASPP2, E2F activates proapoptotic cofactors of p53 T Hershko et al 5 0 -AAATCTTCCCCAGCAAGCC and 5 0 -GCACTTTCTTCTCTTTCTCCC, JMY, 5 0 -ATAAATCCACTCCCATCCCC and 5 0 -CCCCTTTCCTTATTTGT GCC, TP53INP1, 5 0 -AAACCTTCTCATTGAACATCCC and 5 0 -CCATTGT GCTTGACTTGCC, were used in PCR amplifications. Western blot analysis was performed essentially as described.…”

Section: Rt-pcr and Western Blottingmentioning

confidence: 99%

Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F

et al. 2005

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The E2F1 transcription factor is a critical downstream target of the tumor suppressor RB. When activated, E2F1 induces cell proliferation. In addition, E2F1 can induce apoptosis via both p53-dependent and p53-independent pathways. A number of E2F-regulated genes, including ARF, ATM and Chk2, contribute to E2F-induced p53 stabilization. However, it is not known how E2F directs p53 activity towards apoptosis rather than growth arrest. We show that E2F1 upregulates the expression of four proapoptotic cofactors of p53 -ASPP1, ASPP2, JMY and TP53INP1 -through a direct transcriptional mechanism. Adenovirus E1A protein also induces upregulation of these genes, implicating endogenous E2F in this effect. TP53INP1 was shown to mediate phosphorylation of p53 on serine 46. We demonstrate that activation of E2F1 leads to phosphorylation of p53 on serine 46 and this modification is important for E2F1-p53 cooperation in apoptosis. Overall, these data provide novel functional links between RB/E2F pathway and p53-induced apoptosis.

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“…More recently identified E2F targets include genes whose products function in DNA repair (e.g., Msh2, Mlh1, Rad51), cell cycle checkpoints (e.g., Chk1) and mitotic regulation (e.g., Cdc2, cyclin B, Cdc35a, Bub3, Smc2) (Ishida et al, 2001;Kalma et al, 2001;Ma et al, 2002;Weinmann et al, 2002;Wells et al, 2002;reviewed in Stevaux and Dyson, 2002;Cam and Dynlacht, 2003).…”

Section: Introductionmentioning

confidence: 99%

A dynamic switch in Rb+/− mediated neuroendocrine tumorigenesis

et al. 2004

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Rb þ /À mice develop a complex spectrum of neuroendocrine tumors on a mixed genetic (129Sv Â C57BL/6) background. To understand how the 129Sv and C57BL/6 contributions affect Rb þ /À tumorigenesis, we serially backcrossed Rb þ /À animals to the 129Sv or C57BL/6 strain, and analysed their pathological profiles. Strikingly, the length of survival and the penetrance, severity and multiplicity of neuroendocrine tumors switch dramatically between Rb þ /À animals from the two genetic backgrounds. In fact, the 129Sv background significantly enhances both the initiation and progression of tumorigenesis in the intermediate lobe of the pituitary (ILP) in Rb þ /À animals. This is due to the surprising fact that ILPs from wild-type 129Sv animals are inherently abnormal, and thus greatly predisposed to neoplasia. This is likely to explain the high incidence of ILP tumors, an otherwise rare tumor type in wild-type mice, in numerous knockout studies performed on the 129Sv strain, and raises the intriguing possibility that the classic Rb þ /À neuroendocrine tumors may fade away in another as of yet unidentified inbred strain. Finally, we have increased the utility of the Rb þ /À tumor model, since Rb þ /À animals on the C57BL/6 background develop high-penetrance tumors of the anterior lobe of the pituitary, a class of tumors estimated to occur in 20-25% of humans.

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Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2

Cited by 66 publications

References 51 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

Novel link between E2F and p53: proapoptotic cofactors of p53 are transcriptionally upregulated by E2F

A dynamic switch in Rb+/− mediated neuroendocrine tumorigenesis

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