Transcriptional regulation of AKT activation by E2F.

The pRB-E2F pathway is a downstream target of mitogenic signaling pathways. The E2F family of transcription factors has a pivotal role in regulating cell proliferation since it controls the timely expression of many genes that are required for cell cycle progression. Moreover, at least one member of this family, E2F1, can mediate apoptotic cell death. We show here that E2F also modulates the activity of a major signal transduction pathway: we demonstrate that E2F upregulates AKT activity through a transcription-dependent mechanism. We identify the adaptor protein Grb2 associated binder 2 (Gab2) as a direct E2F target gene and an essential effector of E2F-dependent AKT activation. AKT activation was shown to inhibit E2F1induced apoptosis. Therefore, our results suggest the existence of a negative feedback loop involving E2F and AKT.