E2F Mediates Sustained G2 Arrest and Down-regulation of Stathmin and AIM-1 Expression in Response to Genotoxic Stress

Polager, Shirley; Ginsberg, Doron

doi:10.1074/jbc.m210327200

Cited by 64 publications

(66 citation statements)

References 57 publications

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“…The IC 50 of doxorubicin against U-2 OS RB(À) cells was about four fold higher than that against U-2 OS RB( þ ) cells (data not shown). Previous studies using MEFs derived from triple knockout of the RB family (TKO MEF), and NIH3T3 cells expressing HPV E7 protein, suggest that all members of the RB family are involved in DNA damage-induced checkpoint (Sage et al, 2000;Polager and Ginsberg, 2003). Our data indicate that RB loss alone is sufficient to abrogate the G2/M checkpoint in human cells independently of p107 and p130.…”

Section: Establishment Of Stable Rb Knockdown Cell Linessupporting

confidence: 49%

“…Recently, RB was shown to play essential roles in both the G1/S and G2/M checkpoint in response to DNA damage, and in the regulation of proper cell proliferation (Wang et al, 2001). For example, the anticancer agent doxorubicin induces cellular growth arrest at the G1 and G2/M phases by dephosphorylating RB (Polager and Ginsberg, 2003). To analyse the difference in the checkpoints between the established RB( þ )-and (À)-matched cells, we examined the effect of the DNAdamaging agent, doxorubicin, on the cell cycles of these cells.…”

Section: Establishment Of Stable Rb Knockdown Cell Linesmentioning

confidence: 99%

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RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

et al. 2006

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As alterations in retinoblastoma (RB)/E2F pathway are commonly found in human cancers, the molecular mechanism underlying cell cycle deregulation caused by the mutations in the RB/E2F pathway needs to be investigated extensively. Compared with good understanding of RB/E2F functions in G1-S cell cycle progression, it is not fully understood how an abrogated RB pathway affects the G2-M phase of the cell cycle. Here, we report that disruption of RB accelerated G2-M progression in the presence of DNA damage by elevating the expression of a set of mitotic regulatory genes. We generated RB( þ )-and (À)-matched cells using short hairpin RNA. In the RB(À) cells, the G2/M checkpoint mediated by a DNA-damaging agent was over-ridden. With microarray analysis, we found that the expression of key G2-M regulatory genes was upregulated in RB(À) cells. In particular, we demonstrated that the proto-oncogene ECT2 was directly regulated by E2Fs. Furthermore, suppression of ECT2 expression by small interfering RNA in RB(À) cells resulted in cytokinesis arrest, suggesting that RB(À) cells lack the regulation of E2F-mediated cytokinesis. These results indicate that aberrant ECT2 expression, observed in various human tumors, could be the direct result of RB/E2F pathway deficiency, thereby contributing to cell division in cancers.

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Section: Establishment Of Stable Rb Knockdown Cell Linessupporting

confidence: 49%

Section: Establishment Of Stable Rb Knockdown Cell Linesmentioning

confidence: 99%

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

et al. 2006

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“…From this experiment (J Buchsbaum et al, unpublished data), we identified seven mitotic genes that were X2-fold downregulated in irradiated C4-2 cells at both 6 and 24 h following irradiation (Table 1). Expression levels of transcripts that were previously considered to be E2F targets having a role in the G 2 to M checkpoint (Ren et al, 2002;Polager and Ginsberg, 2003) were validated by quantitative real-time polymerase chain reaction (RT-PCR) (Figure 7a). Both methods indicated a similar overall trend of downregulation.…”

Section: Resultsmentioning

confidence: 99%

“…By inactivating the pRB family members that complex with these activating E2Fs through introducing the E7 human papilloma virus (HPV) coupled with DNA damage, the capacity of colorectal cells to undergo G 2 arrest is reduced (Polager and Ginsberg, 2003). Recent work has specifically implicated p130 in the mechanism of G 2 arrest following treatment with either etoposide or adriamycin (Jackson et al, 2005).…”

mentioning

confidence: 99%

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

et al. 2006

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The retinoblastoma (pRB) family proteins regulate the E2F transcription factors; their complexes regulate critical transitions through the cell cycle. The function of these pRB family/E2F complexes, which includes p130/ E2F4, in response to genotoxic agents, is not well understood. We investigated the role of E2F4 in the genotoxic stress response. Following radiation treatment, E2F4 colocalized with p130 in the nucleus during a radiation-induced stable G 2 -phase arrest. Arrested cells had significantly decreased expression of Cyclins A2 and B1 and decreased phosphorylation of mitotic protein monoclonal-2 (MPM-2) mitotic proteins. Small interference RNA (siRNA)-mediated knockdown of E2F4 sensitized cells to subsequent irradiation, resulting in enhanced cellular DNA damage and cell death, as determined by caspase activation and decreased clonogenic cell survival. Downstream E2F4 targets potentially involved in the progression from G 2 into M phase were identified by oligonucleotide microarray expression profiling. Chromatin immunoprecipitation localized E2F4 at promoter regions of the Bub3 and Pttg1 mitotic genes following irradiation, which were among the downregulated genes identified by the microarray. These data suggest that in response to radiation, E2F4 becomes active in the nucleus, enforces a stable G 2 arrest by target gene repression, and thus provides increased cell survival ability by minimizing propagation of cells that have irreparable DNA damage.

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“…These transcription factors are involved in the G1/S transition of the cell cycle and, as discovered more recently, also in the G2/M transition (Ishida et al, 2001;Ren et al, 2002;Polager and Ginsberg, 2003;Thierry et al, 2004;Zhu et al, 2004). There are eight E2F members; E2F1-3 activate the transcription of S-phase genes, whereas E2F4-8 repress their transcription.…”

Section: Introductionmentioning

confidence: 99%

The E2F5 repressor is an activator of E6/E7 transcription and of the S-phase entry in HPV18-associated cells

2010

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High-risk papillomavirus type 18 (HPV18) is one of the less represented HPV types in low-grade lesions of the anogenital tract, whereas it occupies the second place in cervical cancer, where it can be found in 16% of the cases worldwide, after HPV16 present in 54% of them. These epidemiological data indicate that HPV18 infection is more prone to carcinogenic progression. The main oncogenic proteins, E6 and E7 of HPV18, are functionally comparable to the homologous proteins of the other highrisk viruses, including HPV16. In this work, we investigated the possibility that the higher oncogenic potential of HPV18 might be due to transcriptional regulation of the E6/E7 oncogenes. By comparing the E6/E7 promoter and enhancer sequences of the mucosal HPV genomes, we identified E2F binding sites specific for HPV18. The E2F family of transcription factors contains activators (E2F1-3) and repressors (E2F4-8) that regulate the transcription of S-phase and mitotic genes and thereby have a crucial role in cell-cycle progression. Surprisingly, we identified E2F5 as a direct activator of HPV18 E6/E7 transcription by sequential silencing of E2F members in HeLa cells. In addition, we could show that E2F5 positively regulates S-phase entry in HeLa cells and that this activation of the cell cycle by a member of the E2F repressor family is specific for HPV18-expressing cells. Diverting the function of E2F5 from a cell-cycle repressor into an activator might contribute to the higher oncogenic potential of HPV18 when compared with other high-risk HPV types.

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E2F Mediates Sustained G2 Arrest and Down-regulation of Stathmin and AIM-1 Expression in Response to Genotoxic Stress

Cited by 64 publications

References 57 publications

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

RB silencing compromises the DNA damage-induced G2/M checkpoint and causes deregulated expression of the ECT2 oncogene

E2F4 regulates a stable G2 arrest response to genotoxic stress in prostate carcinoma

The E2F5 repressor is an activator of E6/E7 transcription and of the S-phase entry in HPV18-associated cells

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