A Dual Role for the dREAM/MMB Complex in the Regulation of Differentiation-Specific E2F/RB Target Genes

• DOI: 10.1128/mcb.06314-11
• Publication Date: 2012-03-27T03:02:43Z
• Authors: Hangnoh Lee; Linda Ragusano; Ana Martinez; Jagdip Gill; Dessislava K. Dimova
• Keywords: E2F

E2F and RB proteins regulate the expression of genes involved in cell cycle progression, apoptosis, differentiation, development.Recent studies indicate that they function as part an evolutionarily conserved multiprotein complex termed dREAM/ DREAM/LINC.Here we characterize role Drosophila complex, dREAM, regulation differentiation-specific target actively proliferating cells.These are regulated differently from cycle-related targets, do not depend on activation, E2F/RB repression is maintained throughout cycle.In cells, their dependent dREAM.We find dREAM plays a dual regulation.First, it required for stability repressive dE2F2/RBF complexes at promoters during S phase.Second, indispensable both transcriptional mechanisms employed these genes.B oth division exit active proliferation cycles integral parts development multicellular organisms orchestrated by transcription factors spatiotemporal specific sets genes.The families critical regulators processes, activity altered many human tumors (5,7,9,31,40).The pathway was first studied context G 1 /S control (6, 9, 37).E2F can be subdivided into repressors activators transcription.RB family members, also known pocket proteins, negatively two ways.Binding to activator E2Fs inhibits transactivation.When bound repressor E2Fs, recruit corepressors such histone deacetylases (HDACs) or methyltransferases (HMTs) inhibit progression (11).Cyclin-dependent kinases (CDKs) phosphorylate thereby disrupting E2F-RB interactions.This results relief E2F/RB-mediated release transcriptionally triggers entry phase.It now clear functions extend beyond controlling S-phase entry.Biological activities inferred functional mammals other model through identification vast network (2,9,19,34,39), including 2 /M transitions cycle, checkpoint control, DNA repair recombination, development.How all diverse regulated?One answer may lie composite nature network; there eight mammals, five which associate with three different proteins.Individual could perform distinct tasks response various signals.This idea supported several lines evidence ( 9) references therein.Another might provided recent discovery native E2F-RB-containing (14,17,20,22,24).These complexes, called (Drosophila RBF, dE2F2, dMyb-interacting proteins) MMB (Myb-Muv B) flies, DREAM LINC humans, DRM worms, contain E2F, Myb factor, Myb-interacting (Mip40, Mip120, Mip130), p55CAF1 (RbAp46/48).Interestingly, components except related Caenorhabditis elegans synMuv class B vulva development.The appear comprised either E2F4, but both, referred (Myb) (E2F4) (23,38).The switch between E2F4 event (23).While dMyb dE2F2 were initially purified same behave mutually exclusive manner position (15).Accumulating supports have compositions cellular contexts.The repress cycleregulated cells (15,20,22,36; D. K. Dimova, N. J. Dyson, unpublished data); quiescent represses cycle-specific activation /M-specific (probably MMB-Myb-containing complex) (18,26,28,30), regulates site-specific replication follicle (1).Additionally, genome-wide implicated dREAM/DRM wide range been found large number sites genome (15,24,35).We taken advantage relative simplicity system study gene dREAM.Specifically, examined set tar-