ERK activation is regulated by E2F1 and is essential for E2F1-induced S phase entry.

The E2F family of transcription factors regulates a diverse array of cellular functions including cell cycle progression, cell differentiation and apoptosis. Recent studies indicate that E2F1 influences the activity of signal transduction pathways. We identify here a novel link between E2F1 and the Ras/Raf/MEK/ERK signaling pathway, namely that E2F1 levels affect growth factor-induced ERK phosphorylation. Specifically, downregulating E2F1 inhibits PDGF-induced ERK phosphorylation and ectopic expression of E2F1 sensitizes cells to PDGF. We demonstrate that E2F1 induces ERK activation via a transcriptional mechanism and upregulates the expression of two guanine nucleotide exchange factors, RASGRP1 and RASGEF1B, which promote Ras activation. Furthermore, we show that E2F1-induced ERK activity is essential for E2F1-induced S phase entry. Current literature dictates that the cyclin D/pRB/E2F pathway lies downstream of the mitogenically activated Ras/Raf/MEK/ERK cascade. Our results indicate that the relationship between these signaling modules is not a simple unidirectional linear one and suggests there exists a positive feedback loop that may enhance both ERK signaling and E2F1 activity.