Functions And Molecular Mechanisms Of E2F1 In Tumorigenesis

Chronic inflammation or infection-induced mutations or deficiency of pRB is a hallmark of tumors, and that led to disregulation of E2F1. It has been demonstrated from clinical tests that E2F1 is associated with tumorigenesis, development and migrations in a number of tumors including liver, lung, glioma brain, lymphoma and reproduction tumors. Knock-out and transigene mice developed tissue-specific tumors in the later of life. In contrast to the mechanisms of inducing apoptosis by E2F1 have been largely studied., the molecular mechanisms of tumorigenesis of E2F1 are still under investigations. Recent studies showed that, addition to promot cell cycle, E2F1 also crosstalk with some important signaling pathways such as NF-κB, PI3K and ERK in a cell-content dependent fasion. These suggesting that the tumorigenesis role of E2F1 is tissue specific that may involveing signaling crosstalk between E2F1 and major signaling pathways. In this study, we focused on some fundemental mechanisms and functions of E2F1 in tumorigenesis from the view of signaling crosstalks, the results are listed below:(1) Elucidated a novel signaling pathway that E2F1/NF-κB complex transcriptional regulats EGR-1 expression and promotes prostate cancer cell proliferation and antiapoptosisWe showed that E2F1 interacts with NF-κB to form a protein-protein complex and facilities the NF-κB binding site within promoter region of EGR-1 and induces expression of EGR-1. The consistent expression of EGR-1 induces the productions of a panel of growth factors including IGF, PDGF and TNF et al, which promtes cell proliferation and anti-apoptosis in prostate cancers. Futhermore, we also showed that EGR-1 promotes the expression of IL-8 that induces cell growth and metastasis. The results from this studies have published on Cancer Res. 2009 Mar 15;69(6):2324-31 and JBC. 2006;281(15), 10508–10515。(2) The protein–protein complex E2F1/NF-κB suppresses the expression of ICAM-1 that induces immune scapping in prostate cancersIn the study of transcriptional regulation of ICAM-1, we find that E2F1/NF-κB complex is directly binding to the NF-κB site within ICAM-1 promoter and suppresses the expression of ICAM-1 that promote tumor immunescapping in prostate cancer cells. The results in in preperation for publishing on peer-review journals. The studies described in this thesis have elucidated that E2F1/NF-κB crosstalk is a important node in cell signaling pathway, which plays critical roles in tumors through regulating the downstream gene's expression.