The majority of chemotherapeutic drugs work by inducing apoptosis of cancer cells, while sparing non-cancerous cells. However, in many tumors the apoptosis-inducing activity of the p53 pathway has been lost and the resulting tumors are recalcitrant to apoptotic therapies. In contrast to p53, active E2F1 protein is frequently over expressed in cancer cells. Furthermore, recent work has demonstrated that E2F1 can induce apoptosis in a p53-independent manner. Taken together these findings suggest that E2F1 could be an important chemotherapeutic target. The long-term purpose of this proposal is to determine the mechanism by which E2F1 induces apoptosis so that this information can be used to develop more effective chemotherapy. Toward this end, microarray analysis has been used to screen for targets that would explain how E2F1 induces apoptosis in a p53-independent manner. Preliminary work has identified two members of the Bcl-2 family, Mcl-1 and Bok/Mtd, as novel E2F1 targets and direct mediators of E2Fl-induced apoptosis. Specifically, we find that the anti-apoptotic Mcl-1 gene is transcriptionally repressed by E2F1, whereas proapoptotic Bok/Mtd is selectively activated by E2F1 expression. We propose three Specific Aims to explore the novel hypothesis that elevated levels of E2F1 may induce cell death via a p53-independent pathway through transcriptional control of Mcl-1 and Bok/Mtd. Experiments proposed in Specific Aim 1 will determine the mechanism by which E2F1 represses transcription of the Mcl-1 promoter. Since only the DNA binding domain of E2F1 is required to mediate this effect, it is hypothesized that E2F1 blocks Mcl-1 transcription by interfering with Mcl-1 transcriptional activators, such as STAT3 and CREB.
In Specific Aim 2 the hypothesis that the Bok/Mtd promoter contains E2F binding sites and that E2F1 activates the Bok promoter through direct binding and cloning and characterizing the Bok/Mtd promoter will test transcriptional activation.
In Specific Aim 3 a combination of genetic and pharmacological experiments will be used to determine the relative contribution of Mcl-1 down regulation and BoldMtd up regulation to E2Fl-induced apoptosis.
|Chen, Lu; Engel, Brienne E; Welsh, Eric A et al. (2016) A Sensitive NanoString-Based Assay to Score STK11 (LKB1) Pathway Disruption in Lung Adenocarcinoma. J Thorac Oncol 11:838-49|
|Chen, Lu; Kurtyka, Courtney A; Welsh, Eric A et al. (2016) Early2 factor (E2F) deregulation is a prognostic and predictive biomarker in lung adenocarcinoma. Oncotarget 7:82254-82265|
|Ma, Yihong; Chen, Lu; Wright, Gabriela M et al. (2010) CDKN1C negatively regulates RNA polymerase II C-terminal domain phosphorylation in an E2F1-dependent manner. J Biol Chem 285:9813-22|
|Sosa-Garcia, Bernadette; Gunduz, Volkan; Vazquez-Rivera, Viviana et al. (2010) A role for the retinoblastoma protein as a regulator of mouse osteoblast cell adhesion: implications for osteogenesis and osteosarcoma formation. PLoS One 5:e13954|
|Freeman, Scott N; Ma, Yihong; Cress, W Douglas (2008) RhoBTB2 (DBC2) is a mitotic E2F1 target gene with a novel role in apoptosis. J Biol Chem 283:2353-62|
|Ma, Yihong; Kurtyka, Courtney A; Boyapalle, Sandhya et al. (2008) A small-molecule E2F inhibitor blocks growth in a melanoma culture model. Cancer Res 68:6292-9|
|Ma, Y; Cress, W D (2007) Transcriptional upregulation of p57 (Kip2) by the cyclin-dependent kinase inhibitor BMS-387032 is E2F dependent and serves as a negative feedback loop limiting cytotoxicity. Oncogene 26:3532-40|
|Frame, F M; Rogoff, H A; Pickering, M T et al. (2006) E2F1 induces MRN foci formation and a cell cycle checkpoint response in human fibroblasts. Oncogene 25:3258-66|
|Rodriguez, Jose M; Glozak, Michele A; Ma, Yihong et al. (2006) Bok, Bcl-2-related Ovarian Killer, Is Cell Cycle-regulated and Sensitizes to Stress-induced Apoptosis. J Biol Chem 281:22729-35|
|Freeman, Scott N; Bepler, Gerold; Haura, Eric et al. (2005) Re: Prognostic significance of a short sequence insertion in the MCL-1 promoter in chronic lymphocytic leukemia. J Natl Cancer Inst 97:1088-9; author reply 1093-5|
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