The primary goal of the proposed work is to define the mechanisms responsible for specificity of function within the E2F family of transcription factors. The importance of the work lies in the fact that this group of transcription factors, that are targets for control by the Rb tumor suppressor, have been shown to be critical for cell proliferation, including the transition through the G1/S phase and G2/M of the cell cycle. In addition, E2Fs also link the proliferative response with cell fate decisions including apoptosis. Various studies suggest that these various roles are mediated by individual members of the E2F family, at least in part through the control of different sets of target genes. Our recent work points to a mechanism for promoter specificity that involves the coordinated action of E2F proteins with partner transcription factors whereby specific combinations of factors are required for proper promoter function. This concept of combinatorial control has been put forward as a model for achieving the massive complexity of transcription control for the large number of protein-coding genes using a limited number of transcription factors. We now propose to extend these initial studies to more globally define the role of E2F protein interactions in the determination of functional specificity. This will include the use of genome-scale data analysis to predict E2F interactions that impart specificity of transcription control that will then be verified with specific assays of promoter interaction and function. In addition, we will identify structure features of E2Fs and cooperating transcription factors that are essential for this combined action and we will finally explore mechanism that control gene expression through a control of these protein interactions. Given the pervasive role of Rb pathway mutations in human cancer, understanding the specificity of function in the pathway, particularly the action of the E2F proteins, is critical in considering the development of cancer therapeutics that might target the most relevant aspects of Rb function.

Public Health Relevance

The E2F family of transcription factors are now recognized as central to the control of cellular proliferation. Loss of E2F control through deregulation of the Rb pathway is also observed as a common if not mandatory consequence of oncogenesis. As such, the understanding of the mechanisms by which these proteins control gene expression is clearly critical to understanding aspects of cell proliferation control and the contribution to human cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Knowlton, John R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
Schools of Medicine
United States
Zip Code
Shats, Igor; Gatza, Michael L; Liu, Beiyu et al. (2013) FOXO transcription factors control E2F1 transcriptional specificity and apoptotic function. Cancer Res 73:6056-67
Liu, Beiyu; Shats, Igor; Angus, Steven P et al. (2013) Interaction of E2F7 transcription factor with E2F1 and C-terminal-binding protein (CtBP) provides a mechanism for E2F7-dependent transcription repression. J Biol Chem 288:24581-9
Angus, S P; Nevins, J R (2012) A role for Mediator complex subunit MED13L in Rb/E2F-induced growth arrest. Oncogene 31:4709-17
Leung, J Y; Andrechek, E R; Cardiff, R D et al. (2012) Heterogeneity in MYC-induced mammary tumors contributes to escape from oncogene dependence. Oncogene 31:2545-54
Freedman, Jennifer A; Tyler, Douglas S; Nevins, Joseph R et al. (2011) Use of gene expression and pathway signatures to characterize the complexity of human melanoma. Am J Pathol 178:2513-22
Wong, Jeffrey V; Yao, Guang; Nevins, Joseph R et al. (2011) Viral-mediated noisy gene expression reveals biphasic E2f1 response to MYC. Mol Cell 41:275-85
Freedman, Jennifer A; Augustine, Christina K; Selim, Angelica M et al. (2011) A methodology for utilization of predictive genomic signatures in FFPE samples. BMC Med Genomics 4:58
Hallstrom, Timothy C; Nevins, Joseph R (2009) Balancing the decision of cell proliferation and cell fate. Cell Cycle 8:532-5
Freedman, J A; Chang, J T; Jakoi, L et al. (2009) A combinatorial mechanism for determining the specificity of E2F activation and repression. Oncogene 28:2873-81
Andrechek, Eran R; Cardiff, Robert D; Chang, Jeffrey T et al. (2009) Genetic heterogeneity of Myc-induced mammary tumors reflecting diverse phenotypes including metastatic potential. Proc Natl Acad Sci U S A 106:16387-92

Showing the most recent 10 out of 14 publications