Disease relevance of Rbf

• 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].
• Rbf is the Drosophila homologue of the retinoblastoma tumor-suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis [2].

High impact information on Rbf

• Loss of dE2F or overproduction of its corepressor, RBF, retarded cell proliferation [3].
• Here we show that Hh signalling promotes transcription of Cyclin E and Cyclin D, two inhibitors of Rb, and principal regulators of the cell cycle during development in Drosophila [4].
• We identified a mutation in patched (ptc), an inhibitor of Hh signalling, in a genetic screen for regulators of the Retinoblastoma (Rb) pathway in Drosophila [4].
• We have now identified a binding factor (FBF) which is a cytoplasmic protein that binds specifically to the regulatory region of fem-3 3'UTR and mediates the sperm/oocyte switch [5].
• The RNA-binding domain of FBF consists of a stretch of eight tandem repeats and two short flanking regions [5].

Chemical compound and disease context of Rbf

• The human nuclear protein RbAp48 is a member of the tryptophan/aspartate (WD) repeat family, which binds to the retinoblastoma (Rb) protein [6].

Biological context of Rbf

• We propose that dE2F/RBF complexes should not be viewed simply as a cell cycle regulator of transcription [7].
• Mutation of E2f2, Dp, or Rbf1 causes ectopic DNA replication throughout the follicle cell genome during gene amplification cycles [8].
• In Drosophila melanogaster the E2f1, E2f2, Dp, and Rbf1 genes all contribute to replication control in ovarian follicle cells, which become 16C polyploid and subsequently undergo chorion gene amplification late in oogenesis [8].
• Expression of the gene Retinoblastoma-family protein (Rbf) is downregulated in these tumours and, indeed, this downregulation is associated with DNA hypermethylation [9].
• The role of RBF in the introduction of G1 regulation during Drosophila embryogenesis [10].

Physical interactions of Rbf

• Identification of a Drosophila Myb-E2F2/RBF transcriptional repressor complex [11].
• In a recent report, Ferres-Marco et al. described how they used the Drosophila eye as a model system and found that elevated Notch signaling in combination with activation of components of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene [2].

Regulatory relationships of Rbf

• Repression of dMyc expression by Wingless promotes Rbf-induced G1 arrest in the presumptive Drosophila wing margin [12].
• We found that manipulations of endogenous or transgenic NOS activity during imaginal disc development can enhance or suppress the effects of RBF and E2F on development of the eye [13].
• 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] [14].

Other interactions of Rbf

• For some genes the magnitude of this transcriptional derepression is greater in Rbf1 than in E2f2 mutants [8].
• 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 [7].
• A Gradient of Epidermal Growth Factor Receptor Signaling Determines the Sensitivity of rbf1 Mutant Cells to E2F-Dependent Apoptosis [15].
• Here we show that the initial downregulation of expression of the E2f1-target gene RnrS, which occurs during cycles 15 and 16 prior to entry into G1(17), does not require Rbf1 or p27(Dap) [16].
• These results suggest that the ability of Cyclin D/Cdk4 to drive growth in the proliferating wing cells is distinct from that in the none-dividing eye cells or the ability of activated Ras to induce growth, and that RBF may have a role in regulating growth in the proliferating wing discs [17].

Analytical, diagnostic and therapeutic context of Rbf

• Here we show by both reverse transcription-PCR and DNA microarray analysis that the transcripts of prereplication complex (pre-RC) genes are elevated compared to the wild type in E2f2, Dp, and Rbf1 mutant follicle cells [8].

References