The E2F family of transcription factors is regulated by pRb and is characterized by the fact that DNA tumor virus oncoproteins alter the association of E2F with the pRb family of tumor suppressors. pRb is able to bind and inactivate E2F; this ability correlates with the ability of Rb to suppress cell growth, indicating that pRb mediated suppression of tumor growth may be mediated by E2F. The adenovirus E1A oncogenic protein also acts via pRb; binding of E1A to Rb releases E2F. Consistent with this view, the E2F transcription factors directly regulate the transcriptional activity of many genes involved in controlling the cell cycle and cell growth, such as c-myc, c-myb, DHFR, thymidine kinase. In order to study the function of E2F, the principal investigator has established an experimental system of 32D cells overexpressing E2F-1; these cells are normally dependent on IL-3 and will differentiate along the myeloid pathway in the presence of G-CSF. Preliminary data show that overexpression of E2F-1 accelerates apoptosis upon IL-3 withdrawal and co-overexpression of DP-1 (a heterodimer partner of E2F-1) augments the rate of cell death. High levels of E2F/DP-1 can induce apoptosis even in the presence of IL-3. Furthermore, preliminary data suggest that p53 protein accumulates and BCL-2 decreases as a function of E2F activity in 32D cells. It is hypothesized that in the context of Rb and P53 inactivation, deregulation of E2F may provide growth advantage and oncogenesis and also interfere with differentiation. In addition, the principal investigator has found that E2F3 and DP1 mRNA levels are regulated by IL-3 in 32D cells, and thus he proposes to determine the role of these genes in myeloid differentiation, to link the cytokine signaling with nuclear events regulating cell cycle progression. Primary cultures of hematopoietic progenitor cells will be used to test the hypothesis that suicide pathways must be inactivated prior to E2F activation in multistep tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013726-03
Application #
2422810
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Sierra, Felipe
Project Start
1996-04-09
Project End
2001-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Linggi, Bryan; Muller-Tidow, Carsten; van de Locht, Louis et al. (2002) The t(8;21) fusion protein, AML1 ETO, specifically represses the transcription of the p14(ARF) tumor suppressor in acute myeloid leukemia. Nat Med 8:743-50
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Nip, J; Hiebert, S W (2000) Topoisomerase IIalpha mediates E2F-1-induced chemosensitivity and is a target for p53-mediated transcriptional repression. Cell Biochem Biophys 33:199-207
Lutterbach, B; Westendorf, J J; Linggi, B et al. (2000) A mechanism of repression by acute myeloid leukemia-1, the target of multiple chromosomal translocations in acute leukemia. J Biol Chem 275:651-6
Strom, D K; Nip, J; Westendorf, J J et al. (2000) Expression of the AML-1 oncogene shortens the G(1) phase of the cell cycle. J Biol Chem 275:3438-45
Westendorf, J J; Mernaugh, R; Hiebert, S W (1999) Identification and characterization of a protein containing formin homology (FH1/FH2) domains. Gene 232:173-82
Strom, D K; Cleveland, J L; Chellappan, S et al. (1998) E2F-1 and E2F-3 are functionally distinct in their ability to promote myeloid cell cycle progression and block granulocyte differentiation. Cell Growth Differ 9:59-69
Lutterbach, B; Westendorf, J J; Linggi, B et al. (1998) ETO, a target of t(8;21) in acute leukemia, interacts with the N-CoR and mSin3 corepressors. Mol Cell Biol 18:7176-84

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