E2F1, a key transcription factor originally discovered in the adenovirus early region 1A (EIA) transform cells, promotes proliferation by up-regulating a variety of genes, such as Cdc6, Cdc2, and cyclin A2. E2F1 is required for cell cycle transition from G1 to S phase. Enhanced E2F1 activity has been observed in a number of tumors as a result of impaired retinoblastoma tumor suppressor (pRb) function.48 It has been demonstrated that pRb mutation or its absence occurs in at least one-third of all human tumors.49 In normal cells, the binding of pRb to E2F1 is under the control of cell cycle-dependent phosphorylation. In G0 and early G1 phase, hypophosphorylated pRb binds to an 18-amino-acid motif within the transactivation domain of E2F1, resulting in the inhibition of transcriptional activity of E2F1.50 In addition, a number of transcriptional repressors, such as histone deacetylase enzymes (HDACs),51 human brahma related gene (BRG1),52 and histone methyltransferase SUV39H1,53 can associate with suppressed pRb-E2F1. Following the sequential activation of cell cycle-dependent kinase complexes cyclin D/Cdk4 and cyclin E/Cdk2 induced by mitogenic growth factors, pRb is hyperphosphorylated and dissociates from E2F1, leading to the activation of E2F1. Activated E2F1 can form a heterodimer with DP1 or DP2 and bind to various known E2F-responsive promoters of target genes.

The evidence indicating an anti-apoptotic effect of E2F1 was first provided by the studies of E2F1 overexpression.54 Microinjection of the wild type-E2F1 cDNA, but not mutated E2F1 cDNA, into quiescent cells can activate DNA synthesis and induce S-phase entry.54 Further studies indicated that overexpression of E2F1 can cause transformation of primary cells.55 In contrast, mutation of E2F1 is sufficient to block cell proliferation completely.48

The target genes involved in cell cycle transition induced by E2F1 include DNA topoisomerase IIoc, cyclines D and E, Cdc25A, replication protein A, replication factor C, DP1, and DNA polymerase a and 5.5657 In addition to the transcription of cell cycle regulatory genes, E2F1 can also stimulate the expression of genes involved in DNA repair and mitosis. These genes include MAP3 kinase 5, MSH2, MSH6, PCNA, BRCA1, BUB 1b, AIM-1, KRP1, Cdc2, and serine threonine kinase SAK-a.57,58

Interestingly, E2F1 activation also increases the transcription of genes that facilitate cell apoptosis. These pro-apoptotic genes, regulated by E2F1, include caspase 3, AFAF-1, and the p53 family member p73.5759 Thus, although E2F1 appears to be an essential transcription factor required for cell cycle transition and proliferation, E2F1 is also a pro-apoptotic factor. Further support of this conclusion is the fact that E2F1 antagonizes the activity of NF-kB, a well-documented anti-apoptotic transcription factor, by direct association with p65, to abolish the NF-KB-dependent expression of SOD1 that is responsible for the elimination of ROS.60 An alternative mechanism, that E2F1 negatively regulates NF-kB, is its inhibition on TRAF2, an activator of NF-kB upstream kinase, IKK.61

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook

Post a comment