Introduction to the E2F family: protein structure and gene regulation.

E2F is a heterodimer composed of two partners, such as E2F1 and DP1. Although E2F1 can bind DNA as a homodimer and increase promoter activity, optimal DNA-binding and transcriptional activity occurs in the heterodimeric form. A model (Fig. 3) for the involvement of E2F activity in cell growth control that incorporates viral oncoproteins, positive regulators of cell growth (cyclins) and negative regulators of cell growth (tumor suppressor proteins) can now be advanced. Each aspect of this model is addressed in subsequent chapters of this book. It is likely that binding of growth-suppressing proteins, such as Rb, can inhibit the transactivation potential of E2F1, either by blocking the interaction of E2F1 with a separate component of the transcription complex or by bringing a repressor domain to the transcription complex (Flemington et al. 1993; Helin et al. 1993; Weintraub et al. 1992; Zamanian and La Thangue 1993; Zhu et al. 1993). Phosphorylation or sequestration of Rb by viral oncoproteins can free E2F. The influence of viral oncoproteins on E2F activity and the regulation of the different E2F complexes is the focus of the contributions by Cobrinik and by Cress and Nevens. The interaction of the free E2F induces a bend in the DNA that may also play a role in transactivation, perhaps by bringing proteins (such as an Sp1 or CCAAT family member) separated by distance on the promoter DNA into contact (Huber et al. 1994). Because E2F target genes encode proteins critical for cell growth, deregulation of E2F activity can have severe consequences, such as apoptosis or uncontrolled proliferation. The effect of altered expression of E2F activity on the cell cycle and on tumorigenicity is the focus of the contribution by Adams and Kaelin. Finally, a comparison of E2F to the genetically well-characterized factors that regulate G1/S phase transcription in yeast is the subject of the chapter by Breeden. This volume concludes with Farnham's summary of the rapid gains in knowledge concerning the E2F gene family that have been made in the past several years and provides a series of questions and lines of investigation that will be the focus of future studies.