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.
Korotayev
Katya
K
The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan 52900, Israel.
Chaussepied
Marie
M
Ginsberg
Doron
D
D045744:Cell Line, Tumor; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D016196:S Phase / Q000235:genetics; D014158:Transcription, Genetic; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism
D050687:E2F1 Transcription Factor; D010982:Platelet-Derived Growth Factor; D020663:ras Guanine Nucleotide Exchange Factors; D048049:Extracellular Signal-Regulated MAP Kinases