NUCLEAR ACCUMULATION OF THE E2F HETERODIMER REGULATED BY SUBUNIT COMPOSITION AND ALTERNATIVE SPLICING OF A NUCLEAR-LOCALIZATION SIGNAL

The cellular transcription factor E2F plays a critical role in integra ting cell cycle progression with the transcription apparatus by virtue of a physical interaction and control by key regulators of the cell c ycle, such as pRb, cyclins and cyclin-dependent kinases. Generic E2F D NA binding activity arises when a member of two families of proteins, E2F and DP, form heterodimeric complexes, an interaction which results in co-operative transcriptional and DNA binding activity. Here, we ch aracterise a new and hitherto unexpected mechanism of control influenc ing the activity of E2F which is mediated at the level of intracellula r location through a dependence on heterodimer formation for nuclear t ranslocation. Nuclear accumulation is dramatically influenced by two d istinct processes: alternative splicing of a nuclear localization sign al and subunit composition of the E2F heterodimer. These data define a new level of control in the E2F transcription factor whereby interpla y between subunits dictates the levels of nuclear DNA binding activity .