E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis

Müller, Heiko; Bracken, Adrian P.; Vernell, Richard; Moroni, Maria Cristina; Christians, Fred C.; Grassilli, Emanuela; Prosperini, Elena; Vigo, Elena; Oliner, Jonathan D.; Helin, Kristian

doi:10.1101/gad.864201

Cited by 684 publications

(618 citation statements)

References 60 publications

Supporting

Mentioning

580

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

Section: Transcriptional Targets Of Rb and E2f Proteinsmentioning

confidence: 99%

Retinoblastoma family genes

2006

View full text Add to dashboard Cite

“…Overexpression of E2F drives cell proliferation, and thus the induction of reporter activity shown above had the possibility of secondary transcriptional change caused by an accelerated cell cycle (Muller et al, 2001). In order to verify whether RB/E2F directly regulates the ECT2 promoter, we used a chromatin immunoprecipitation (ChIP) assay.…”

Section: Rb Disruption Induces Aberrant Ect2 Expression T Eguchi Et Almentioning

confidence: 99%

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

et al. 2006

View full text Add to dashboard Cite

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.

show abstract

“…However, E2F1À/À knockout mice develop a broad spectrum of tumors, suggesting that E2F1 also functions as a tumor suppressor. Indeed, several authors reported that E2F1 can induce apoptosis through p53-dependent (Kowalik et al, 1995;Qin et al, 1994;Wu and Levine, 1994) and p53-independent mechanisms (Irwin et al, 2000), by upregulating apoptotic genes like Apaf-1 (Furukawa et al, 2002), p73 (Stiewe and Putzer, 2000), caspase 3 and 7 (Muller et al, 2001), Noxa and PUMA (Hershko and Ginsberg, 2004). Furthermore, forced expression of E2F1 caused increased sensitivity to DNA-damaging agents and topoisomerase II inhibition in a p53-independent manner (Nip et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

et al. 2006

View full text Add to dashboard Cite

MDM2 is a critical negative regulator of the p53 tumor suppressor protein. Recently, small-molecule antagonists of MDM2, the Nutlins, have been developed to inhibit the p53-MDM2 interaction and activate p53 signaling. However, half of human cancers have mutated p53 and they are resistant to Nutlin treatment. Here, we report that treatment of the p53-mutant malignant peripheral nerve sheath (MPNST) and p53-null HCT116 cells with cisplatin (Cis) and Nutlin-3a induced a degree of apoptosis that was significantly greater than either drug alone. Nutlin-3a also increased the cytotoxicity of both carboplatin and doxorubicin in a series of p53-mutant human tumor cell lines. In the human dedifferentiated liposarcoma cell line (LS141) and the p53 wild-type HCT116 cells, Nutlin-3a induced downregulation of E2F1 and this effect appeared to be proteasome dependent. In contrast, in MPNST and HCTp53À/À cells, Nutlin-3a inhibited the binding of E2F1 to MDM2 and induced transcriptional activation of free E2F1 in the presence of Cis-induced DNA damage. Downregulation of E2F1 by small interfering RNA significantly decreased the level of apoptosis induced by Cis and Nutlin-3a treatment. Moreover, expression of a dominant-negative form of E2F1 rescued cells from apoptosis, whereas cells overexpressing wildtype E2F1 showed an increase in cell death. This correlated with the induction of the proapoptotic proteins p73a and Noxa, which are both regulated by E2F1. These results indicate that antagonism of MDM2 by Nutlin-3a in cells with mutant p53 enhances chemosensitivity in an E2F1-dependent manner. Nutlin-3a therefore may provide a therapeutic benefit in tumors with mutant p53 provided it is combined with chemotherapy.

show abstract

E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis

Cited by 684 publications

References 60 publications

Retinoblastoma family genes

Retinoblastoma family genes

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

Mouse double minute antagonist Nutlin-3a enhances chemotherapy-induced apoptosis in cancer cells with mutant p53 by activating E2F1

Contact Info

Product

Resources

About