E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product.

Flemington, Erik K.; Speck, Samuel H.; Kaelin, William G.

doi:10.1073/pnas.90.15.6914

Cited by 328 publications

(246 citation statements)

References 33 publications

(35 reference statements)

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“…First, pRb binds to an 18 amino-acid motif within the transactivation domain of E2F, blocking the ability of E2F to recruit the basic transcriptional machinery. 17,18 E2F in this context is considered a 'passive' repressor as it can occupy E2F DNA-binding sites, but cannot activate gene expression. Second, the pRb-E2F complex, while still bound to DNA, recruits various factors, for example, histone deacetylases (HDACs), SWI/ SNF, Polycomb group proteins and histone methyl transferase (SUV39H10), which are able to switch off transcription and as a result effect 'active' repression ( Figure 1).…”

Section: E2fs In Cell Cycle Controlmentioning

confidence: 99%

Life and death decisions by E2F-1

2003

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Deregulation of the transcription factor E2F-1 is a common event in most human cancers. Paradoxically, E2F-1 has been shown to have the ability to induce both cell cycle progression and programmed cell death, leading potentially to both tumour-promoting as well as tumour-suppressive effects. Although the pathway to cell cycle progression seems straightforward with a number of growth-promoting E2F target genes having been described, the pathways to apoptosis are less well defined and more complex. The discovery that E2F-1 'knockout' mice are highly tumour prone has caused a recent surge in the number of reports relating to programmed cell death. This review focuses on these recent findings, highlighting the way in which they have increased our understanding of E2F-1-induced cell death, as well as indicating the questions that remain. Insight gained as to the role of this intriguing molecule in cancer and its potential for targeted therapy will also be discussed.

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Section: E2fs In Cell Cycle Controlmentioning

confidence: 99%

Life and death decisions by E2F-1

2003

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“…The presence of p21 abrogated transcription from the cyclin A promoter, an e ect that was alleviated by co-expression of E2F-1 (Figure 1a, compare tracks 1, 2 and 3) and speci®c for the E2F binding site (data not shown). Since p21 can in¯uence the level of hypophosphorylated pRb through the inactivation of G1 cdks (Sherr and Roberts, 1995), and because E2F-1 can physically interact with pRb (Flemington et al, 1993;Helin et al, 1993), such an e ect could have arisen if the level of E2F-1 was su cient to titrate and thus inactivate the repressing form of pRb. To rule out this possibility, two di erent mutant E2F-1 proteins, Y411C and D5, which are severely compromised in their pRb binding capacity (Helin et al, 1993;Krek et al, 1994), were co-expressed with p21.…”

Section: Control Of E2f Activity By P21mentioning

confidence: 99%

Control of E2F activity by p21Waf1/Cip1

1999

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Cyclin-dependent kinase inhibitors (cdkis), such as p21, are believed to control proliferation through an ability to function as stoichiometric antagonists of cyclin-dependent kinases (cdks). The p21 gene is a direct transcriptional target for the p53 protein, and its activation is likely to be important in e ecting the p53 response. It is widely accepted that p21 can in¯uence cell cycle progression by controlling the activity of cdks that act on the retinoblastoma tumour suppressor protein (pRb) which, in a hypophosphorylated state, associates with E2F transcription factors to prevent the activation of genes required for progression into S phase. Phosphorylation of pRb by G1 cdk complexes releases E2F and thereby enables progress through the cell cycle. Here, we describe results which suggest a p21-dependent mechanism that facilitates the regulation of E2F through a pathway that is independent of the cdk control of pRb activity. As p21 can associate with E2F subunits, it is possible that these e ects are exerted through a complex with E2F. Furthermore, we ®nd that p21 can regulate transcription in vitro. The results suggest that p21 may control E2F activity through a pathway that acts independently of pRb.

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“…The only known substrate for the activated Cdk4 is the retinoblastoma protein, pRB (Matsushime et al, 1992;Dowdy et al, 1993;Kato et al, 1993). In its hypophosphorylated form, pRB can bind and inhibit transcription factors, including heterodimers of the E2F and DP families of proteins (Farnham et al, 1993;Flemington et al, 1993). Phosphorylation of pRB during G1 leads to release of E2F/DP and subsequent activation of genes that participate in S phase entry (Farnham et al, 1993;Huber et al, 1993;Lam and La Thangue, 1994).…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

Sakai

et al. 1998

Oncogene

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Transforming growth factor-beta 1 (TGF-b1) arrests intestinal epithelial cells (RIE-1 and IEC-6) in the G1 phase of the cell cycle and inhibits cyclin D1 expression. This report describes experiments designed to elucidate the mechanism of cyclin D1 inhibition and to determine whether inhibition of cyclin D1 expression is the cause, rather than the result, of TGF-b1-mediated cell cycle arrest. TGF-b1 inhibition of IEC-6 cell proliferation was associated with a decrease in the abundance of cyclin D1/Cdk4 complexes and a corresponding decrease in Cdk4-dependent phosphorylation of the retinoblastoma protein. Metabolic labeling studies indicated that TGFb1 inhibited cyclin D1 synthesis without altering the rate of cyclin D1 protein degradation. Cyclin D1 antisense oligonucleotides blocked serum-stimulated induction of cyclin D1 and DNA synthesis, whereas cyclin D1 sense oligonucleotides had no e ect. RIE-1 cells were engineered to overexpress human cyclin D1 under the control of a tetracycline-repressible promoter. These cells entered S phase in the presence of TGF-b1 only when human cyclin D1 was derepressed by the withdrawal of tetracycline. These data indicate that TGF-b1 inhibits the synthesis of cyclin D1 in gut epithelial cells and that this inhibition is the cause, rather than the result, of TGF-b1-mediated arrest of intestinal epithelial cell proliferation.

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E2F-1-mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product.

Cited by 328 publications

References 33 publications

Life and death decisions by E2F-1

Life and death decisions by E2F-1

Control of E2F activity by p21Waf1/Cip1

TGF-β1 effects on proliferation of rat intestinal epithelial cells are due to inhibition of cyclin D1 expression

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