The long-term objectives of the proposed research are to define the molecular mechanisms underlying the normal relationship between proliferation and apoptosis and to understand the consequences of uncoupling this connection in diseases like cancer. Mounting evidence points to central roles of the Rb/E2F pathway in the commitment of cells to S phase and for p53 to limit the proliferative capacity of this pathway by inducing growth arrest or apoptosis. In support of this relationship, we have previously shown that expression of E2F1 not only leads to S phase induction, but also to a p53-dependent apoptosis. This apoptosis is specific to E2F1 and coincides with an E2F1-mediated accumulation of p53 protein. Both of these processes appear to be stimulated by E2F1 transcriptional activity. Using recombinant adenoviruses to efficiently express cDNAs in mouse embryo fibroblasts (MEFs) that are nullizygous for p19ARF, p53 or double null for Mdm2/p53, we now have evidence to suggest that E2F1 signals apoptosis and p53 accumulation through separate pathways. It has been suggested that E2F1 induces p53 accumulation and apoptosis by activating the p19ARF pathway. However, we find that although p19ARF is downstream of E2F1 in signaling p53 accumulation, p19ARF is not necessary for E2F1- mediated apoptosis. Interestingly, we do find that Mdm2 is required for both E2F1-mediated p53 accumulation and apoptosis. This implies that the p53 accumulation and apoptosis pathways diverge at the point where Mdm2 affects p53 function. To further investigate the different pathways by which E2F1 induces p53 accumulation and apoptosis, I plan to 1) characterize the pathway by which E2F expression leads to p53 protein accumulation and analyze the consequences of inducing this pathway; 2) determine the steps involved in a p19ARF-independent pathway that leads to p53-dependent apoptosis; and 3) identify apoptosis genes that are specifically induced by E2F1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA086038-01
Application #
6097365
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Spalholz, Barbara A
Project Start
2000-02-05
Project End
2005-01-31
Budget Start
2000-02-05
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$286,010
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
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