The disruption of various components of the pathway controlling E2F accumulation, either the activation of positive acting components such as the G1 cyclins or the inactivation of negative components such as Rb and the cdk inhibitors, can lead to the loss of cell growth control underlying the development of various forms of human cancer. Mammalian E2F is composed of a family of heterodimers encoded by distinct genes. Each E2F protein appears to activate a distinct set of target genes and E2F uniquely induces apoptosis. In addition, recent studies describing the consequences of the disruption of the E2F1 gene in the mouse suggest a role for E2F1 in the induction of apoptosis in the physiological context of thymocyte maturation. Given the importance of E2F in the control of proliferation and cell fate, it is critical that we understand the mechanism underlying transcriptional specificity of the different E2F family members which contributes to their specific roles. The proposed studies will be directed at understanding the role of the E2F transcription factor family in cell growth and cell fate determination. These studies will involve four specific aims: 1) the identification of the specific genes regulated by the individual E2F family members in large part using the recently described SAGE (Serial Analysis of Gene Expression) technology. 2) an investigation of the mechanism underlying transcriptional specificity including a determination of the relative contributions of different protein domains to target specificity. 3) characterization of the specific role of E2F1 as a mediator of apoptosis during the selection of the T cell repertoire, in part by utilizing T cell receptor transgenic mice. 4) a molecular analysis of how E2F activities are both controlled by and contribute to pathways which lead to apoptosis in lymphocytes by employing a thymocyte in vitro negative selection assay. These studies will further our understanding of the individual contributions of the different E2F family members towards the control of cell growth and apoptosis, and should help elucidate the pathways which regulate apoptosis in lymphocytes, the deregulation of which contributes to both autoimmune disease and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA077314-04
Application #
6362645
Study Section
Molecular Biology Study Section (MBY)
Project Start
1998-05-01
Project End
2003-02-28
Budget Start
2001-03-01
Budget End
2002-02-28
Support Year
4
Fiscal Year
2001
Total Cost
$192,338
Indirect Cost
Name
University of Colorado Denver
Department
Biochemistry
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
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

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