Loss of retinoblastoma (Rb) tumor suppressor function leads to deregulated cell proliferation and contributes to the development of most human cancers. In response to Rb inactivation, the p53 tumor suppressor is activated and this usually results in the elimination of the cell by apoptosis. This """"""""guardian of Rb"""""""" function for p53 plays a critical role in suppressing tumorigenesis. Experimental evidence demonstrates that the signaling pathway from Rb inactivation to p53 activation requires the E2F1 transcription factor. Deregulation of E2F1, by overexpression or Rb inactivation, results in p53 accumulation and the induction of apoptosis. It has been widely speculated that the alternative reading frame (ARF) tumor suppressor, an inhibitor of mdm2, mediates the activation of p53 by E2F1. This suggestion is based on the findings that E2F1 transcriptionally activates the ARF gene promoter and that other oncogenes, such as Myc, require ARF to induce p53-dependent apoptosis. In preliminary data we demonstrate that ARF is in fact dispensable for E2F1-induced apoptosis. Instead, the induction of p53-dependent apoptosis by E2F1 is correlated with the caffeine-sensitive phosphorylation of p53. Moreover, the ataxia-telangiectasia mutated (ATM) kinase, which has been implicated in activating p53 in response to DNA damage, is found to be required for E2F1-induced p53 phosphorylation and apoptosis. In contrast, the ability of E2F 1 to stimulate the expression of target genes and to promote S phase entry is unaffected by the absence of ATM. The product of the Nijmegen breakage syndrome gene, NBS1, is also shown to be required for E2F1 to induce the phosphorylation of p53 and apoptosis. NBS1 is part of the Mre11/Rad50 DNA repair complex and has recently been shown to directly bind E2F1. These findings expand the known functions for ATM and NBS1 and significantly alter the current model for how cell cycle deregulation activates p53. Our hypothesis is that deregulated E2F1 activity stimulates ATM in an NBS1-dependent manner to activate p53 and perhaps other checkpoint response factors. This E2F1-ATM pathway may respond to both cell cycle deregulation and DNA damage to induce apoptosis and suppress tumorigenesis. A major goal of these studies will be to molecularly define the roles of ATM and NBS1 in the signaling pathway between E2F1 and p53. A role for p73 and c-Abl in E2F1-induced, ATM-dependent apoptosis will also be explored. Finally, the functional relationship between E2F1, ATM and NBS1 in modulating tumor development will be examined using murine models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA098601-01A1
Application #
6682988
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Pelroy, Richard
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
1
Fiscal Year
2003
Total Cost
$335,975
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
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Hong, Sungki; Paulson, Qiwei X; Johnson, David G (2008) E2F1 and E2F3 activate ATM through distinct mechanisms to promote E1A-induced apoptosis. Cell Cycle 7:391-400
Hong, Sungki; Pusapati, Raju V; Powers, John T et al. (2006) Oncogenes and the DNA damage response: Myc and E2F1 engage the ATM signaling pathway to activate p53 and induce apoptosis. Cell Cycle 5:801-3
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
Pusapati, Raju V; Rounbehler, Robert J; Hong, SungKi et al. (2006) ATM promotes apoptosis and suppresses tumorigenesis in response to Myc. Proc Natl Acad Sci U S A 103:1446-51
Powers, John T; Hong, SungKi; Mayhew, Christopher N et al. (2004) E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Mol Cancer Res 2:203-14