Decoding the functional specificity of E2F3 isoforms

E2F3 is a central regulator of cell cycle progression, development, differentiation, and oncogenesis. Alternative promoter usage generates two major homologous isoforms, E2F3A and E2F3B, differing only at their N-termini. Although E2F3A is traditionally considered an activator and E2F3B a repressor of transcription, studies suggest that both isoforms have overlapping and isoform-specific functions, shaped by differences in temporal expression, protein stability, and target gene specificity. In this review, we examine how E2F3A and E2F3B contribute to proliferation, differentiation, and cancer. We also discuss contradictions and limitations in experimental approaches that have complicated the interpretation of these functions. Finally, we explore how clarifying these roles could help resolve long-standing questions in cell cycle regulation, differentiation, and cancer, where E2F3 plays a major role.