A genetic screen for modifiers of E2F in Drosophila melanogaster

The activity of the E2F transcription factor is regulated in part by pRB, t he protein product of the retinoblastoma tumor suppressor gene. Studies of tumor cells show that the pi 6(ink4a)/cdk4/cyclin D/pRB pathway is mutated in most forms of cancer, suggesting that the deregulation of E2F, and hence the cell cycle, is a common event in tumorigenesis. Extragenic mutations t hat enhance or suppress E2F activity are likely to alter cell-cycle control and may, play a role in tumorigenesis. We used an E2F overexpression pheno type in the Drosophila eye to screen for modifiers of E2F activity. Coexpre ssion of dE2F and its heterodimeric partner dDP in the fly eye induces S ph ases and cell death. We isolated 33 enhancer mutations of this phenotype by EMS and X-ray mutagenesis and by screening a deficiency library collection . The majority of these mutations sorted into six complementation groups, f ive of which have been identified as alleles of brahma (brm), moira (mor) o sa, pointed (pnt), and polycephalon (poc). osa, brm, and mor encode protein s with homology to SWI1, SWI2, and SWI3, respectively, suggesting that the activity of a SWI/SNF chromatin-remodeling complex has an important impact on E2F-dependent phenotypes. Mutations in poc also suppress phenotypes caus ed by p21(CiP1) expression, indicating an important role for polycephalon i n cell-cycle control.