Disease relevance of E2f

• The role of active repression during normal development has not been analyzed in detail. dE2F1(su89) is a novel allele of dE2F1 that disrupts dE2F1's association with RBF [the Drosophila retinoblastoma protein (Rb) homolog] but retains its transcription activation function [1].
• The co-expression of baculovirus p35 protein, an inhibitor of cell death, strongly enhanced the dE2F/dDP-dependent phenotype [2].

High impact information on E2f

• Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing [3].
• Without dE2F1, the compensatory mechanism fails, and treatments that alter Cdk activity cause aberrant cell cycle timing and cell death [3].
• Loss of dE2F or overproduction of its corepressor, RBF, retarded cell proliferation [4].
• Variations in dE2F activity could be used to coordinate cell division with growth [4].
• The implication of these results is that cells containing dE2F2 require dE2F1 to either prevent, or reverse, dE2F-mediated repression [5].

Biological context of E2f

• We propose that dE2F/RBF complexes should not be viewed simply as a cell cycle regulator of transcription [6].
• Although mutations in dDP or dE2F nearly eliminate E2F-dependent G1-S transcription, S-phase still occurs [7].
• As a result, dE2F/RBF regulation is used to link gene expression with cell cycle progression at some targets while simultaneously providing stable repression at others [6].
• However, mice in which the E2F-1 gene had been disrupted developed tumors, suggesting a negative role for E2F in controlling cell proliferation in some tissues [7].
• Mutation of the Drosophila melanogaster dE2F gene eliminates transcriptional activation of several replication factors at the G1-S transition and compromises DNA replication [8].

Anatomical context of E2f

• Transcriptional repressor functions of Drosophila E2F1 and E2F2 cooperate to inhibit genomic DNA synthesis in ovarian follicle cells [9].
• Interestingly, a dE2F mutant predicted to lack the carboxy-terminal transcriptional activation and RB-binding domain does not abolish ORC2 localization and shows premature chorion amplification [10].
• Ectopic expression of the N-terminal fragment in salivary gland cells reduced the contents of mRNAs for the 180-kDa subunit of DNA polymerase alpha and for dE2F and the extent of DNA endoreplication [11].
• The transcription factor E2F plays a key role in transcriptional control during the growth cycle of higher eukaryotic cells [12].
• Immunodetection studies revealed that endogenous E2F1 and E2F2 proteins were cytoplasmic in myoblasts and myotubes, whereas E2F4 was abundant in the nuclei of both [13].

Associations of E2f with chemical compounds

• This replication inhibition could be overcome by the kinase inhibitor 6-dimethylaminopurine (6-DMAP), but not by expression of subunits of the transcription factor E2F [14].
• This study suggests that, in fruit fly embryos, 1) there is a dose-dependent relationship between cell cycle length and O2 levels in fruit fly embryos, and 2) stabilized cyclin A and E2F1 are likely to be the mediators of hypoxia-induced arrest at metaphase and pre-S phase [15].

Physical interactions of E2f

• In this study, we found three potential Caudal binding sequences in the 5'-flanking region of the Drosophila E2F (DE2F) gene and showed by transient transfection assays that they are involved in Caudal transactivation of the dE2F gene promoter [16].
• We show that a Drosophila DP protein which can interact co-operatively with E2F proteins is a physiological DNA binding component of Drosophila DRTF1/E2F [17].
• Cdc2 binds to E2F in vitro, and post-transcriptionally promotes its accumulation in vivo [18].

Regulatory relationships of E2f

• Caudal-induced E2F expression was also confirmed with a GAL4-UAS system in living flies [16].
• In mammalian cells, the retinoblastoma protein (Rb) is thought to negatively regulate progression through the G1 phase of the cell cycle by its association with the transcription factor E2F [1-3] [19].
• The obtained results indicate that the DRE/DREF system activates transcription of the dE2F gene [20].
• In addition, Cdc2 and Cyclin A cooperatively inhibit transcriptional activation by the essential S phase regulator E2F [18].

Other interactions of E2f

• Mutations in Drosophila DP and E2F distinguish G1-S progression from an associated transcriptional program [7].
• Instead, dE2F/RBF-mediated repression is exerted on genes that encode an assortment of cellular functions, and these effects are reversed on sets of functionally related genes in particular developmental contexts [6].
• More over, RBF2 and dE2F2 act synergistically to antagonize dE2F1-mediated activation, and they co-operate to block S phase progression in transgenic animals [21].
• These results suggest that Caudal is involved in regulation of proliferation through transactivation of the E2F gene in Drosophila [16].
• This regulation of the VG-SD activity by dE2F1 is dependent on the vg genetic background [22].

References