E2F activity is critical for the control of the G1 to S phase transition, and the pathway leading to E2F activation is deregulated in most human tumors. The combined loss of E2F1 and E2F2 results in profound effects on hematopoietic cell proliferation, pancreatic maintenance, tumor suppression, and lymphocyte tolerance. Roles for E2F1 and E2F2 in limiting T-cell proliferation are in contrast to clear roles in facilitating S phase progression, as hematopoietic progenitor cells in E2F1/2 mutant mice demonstrate remarkably delayed S phase progression, contributing to highly inefficient hematopoiesis. Finally, E2F1 and E2F2 appear to be specifically required for the regulation of specific target genes, such as Cyclin A2, which may underlie roles for E2F1/2 in S phase progression. The mechanism underlying E2F1/2 dependent transcriptional specificity will be explored. We propose experiments to characterize E2F1/2 dependent target genes and link the E2F 1/2 dependent regulation of target genes with roles for E2F 1/2 in cell cycle progression, with the eventual goal of connecting these transcriptional and cellular roles with organismal phenotypes observed in E2F1/2 KO mice. We propose three specific aims: 1) Identification and characterization of E2F1 and E2F2 target genes that negatively regulate lymphocyte proliferation. 2) Interrogation of identified target genes as potential mediators of E2F 1/2 dependent control of T-cell proliferation in response to antigen. 3) Exploration of the mechanisms that underlie roles for E2F2 in facilitating S phase progression and hematopoiesis. These studies will combine the powers of gene targeted mice, genome wide analysis of gene expression, inhibition of gene expression by RNAi, and technology developed in our lab that facilitates gene transfer to primary T-cells. Understanding the cellular functions of E2F1/2 and their target genes should facilitate a better understanding of organismal roles for these E2Fs at a more mechanistic level.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
Tessem, Jeffery S; Jensen, Jan N; Pelli, Hanna et al. (2008) Critical roles for macrophages in islet angiogenesis and maintenance during pancreatic degeneration. Diabetes 57:1605-17
Hoglinger, Gunter U; Breunig, Joshua J; Depboylu, Candan et al. (2007) The pRb/E2F cell-cycle pathway mediates cell death in Parkinson's disease. Proc Natl Acad Sci U S A 104:3585-90
Johnson, David G; Degregori, James (2006) Putting the Oncogenic and Tumor Suppressive Activities of E2F into Context. Curr Mol Med 6:731-8
DeGregori, James; Johnson, David G (2006) Distinct and Overlapping Roles for E2F Family Members in Transcription, Proliferation and Apoptosis. Curr Mol Med 6:739-48
Shapiro, Gary S; Van Peursem, Crystal; Ornelles, David A et al. (2006) Recombinant adenoviral vectors can induce expression of p73 via the E4-orf6/7 protein. J Virol 80:5349-60
DeGregori, James (2006) Surprising dependency for retinoblastoma protein in ras-mediated tumorigenesis. Mol Cell Biol 26:1165-9
Bilousova, Ganna; Marusyk, Andriy; Porter, Christopher C et al. (2005) Impaired DNA replication within progenitor cell pools promotes leukemogenesis. PLoS Biol 3:e401
Pappa, Aglaia; Brown, Donald; Koutalos, Yiannis et al. (2005) Human aldehyde dehydrogenase 3A1 inhibits proliferation and promotes survival of human corneal epithelial cells. J Biol Chem 280:27998-8006
Miyamoto, Takeshi; Kaneko, Takaaki; Yamashita, Masakatsu et al. (2005) Prolonged skin allograft survival by IL-10 gene-introduced CD4 T cell administration. Int Immunol 17:759-68
DeGregori, James (2005) E2F and cell survival: context really is key. Dev Cell 9:442-4

Showing the most recent 10 out of 32 publications