E2F-1 Potentiates Cell Death by Blocking Antiapoptotic Signaling Pathways

Phillips, Andrew C.; Ernst, Mary; Bates, Stewart; Rice, Nancy R.; Vousden, Karen H.

doi:10.1016/s1097-2765(00)80387-1

Cited by 220 publications

(199 citation statements)

References 56 publications

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“…25,36,62 Moreover, Myc-induced p53-dependent apoptosis is increased in the epithelium of mice lacking E2F1, 63 while the role of E2F1 in mediating tumorigenesis can be explained by its ability to suppress rather than induce apoptosis. [64][65][66] Collectively, these data imply that E2Fs play complex roles in gene regulation and that apoptotic target genes of E2F1, such as p73, Apaf-1, and procaspases, may be downregulated (rather than upregulated) by E2F1 in vivo, while p53 acts to relieve this expression block. Consistent with this view, DNA binding is required for E2F1-responsive apoptosis, whereas transactivation is largely dispensable.…”

Section: Discussionmentioning

confidence: 93%

MIF loss impairs Myc-induced lymphomagenesis

et al. 2005

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Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the El-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null El-Myc Bcells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type El-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Mycmediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.

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Section: Discussionmentioning

confidence: 93%

MIF loss impairs Myc-induced lymphomagenesis

et al. 2005

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“…The most widely recognized function of cyclin D-dependent kinases is phosphorylation of pRb which disrupts association of pRb with E2F family proteins (Sherr and Roberts, 1999). One member of the E2F family, E2F-1, has been implicated in activation of apoptosis which is negatively regulated by pRb (Phillips et al, 1999;Fan and Steer, 1999). However, hypophosphorylated pRb is also able to induce apoptosis by stabilizing p53 (Hsieh et al, 1999), a function which might be abrogated by cyclin D-dependent phosphorylation of pRb.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

et al. 2000

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Ectopically expressed eukaryotic translation initiation factor 4E (eIF4E) stimulates cell proliferation, suppresses apoptosis in growth factor restricted cells, and induces malignant transformation in primary rodent ®broblasts when coexpressed with protooncogene myc. We report here that eIF4E rescued rat embryo ®broblasts ectopically expressing c-Myc ( signi®cantly increased chemosensitivity; either soluble antisense cyclin D1 oligomers or transfection with a dominant negative cyclin D1 mutant that prevents translocation of cyclin D-dependent kinases to the nucleus, signi®cantly blunted the antiapoptotic e ect of eIF4E. These data directly link eIF4E rescue from cytostatic drugs to cyclin D1. Since overexpression of eIF4E and cyclin D1 is observed in many aggressive forms of chemoresistant cancers, these ®ndings provide insight into possible mechanisms responsible for this biological behavior.

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“…64 E2F-1 can downregulate Traf2 protein levels and therefore inhibit the activation of antiapoptotic signals, such as NF-kB in response to TNFa. 65 It is interesting to note that this effect, similar to E2F-1's ability to inhibit transformation, does not require E2F-1's transactivation domain. 65 The extent, however, to which this mechanism is involved in tumour suppression by E2F-1 is very interesting, but has yet to be determined.…”

Section: A Role In Cancermentioning

confidence: 92%

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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E2F-1 Potentiates Cell Death by Blocking Antiapoptotic Signaling Pathways

Cited by 220 publications

References 56 publications

MIF loss impairs Myc-induced lymphomagenesis

MIF loss impairs Myc-induced lymphomagenesis

Inhibition of Myc-dependent apoptosis by eukaryotic translation initiation factor 4E requires cyclin D1

Life and death decisions by E2F-1

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