The tumor suppressor, pRB, and its related proteins, p107 and p130, play a pivotal role in the regulation of terminal differentiation, proliferation and tumorigenesis through their ability to control the E2F transcription factors. This proposal focuses on understanding how E2F4, the most abundant of the E2F family members, contributes to the growth suppressive properties of the pRB family of proteins. In the last few years, the Lees lab has generated a panel of compound mutant mouse strains, E2f4;Rb, E2f4;p107;p130 and E2f4;E2f5. The preliminary analysis of these animals shows that E2F4 has a profound influence on the regulation of cell cycle exit, the terminal differentiation of numerous cell lineages and the formation of pRB-deficient tumors. They also suggest that the E2F4 complexes are regulating differentiation through two distinct mechanisms: (i) they repress E2F-responsive genes to mediate cell cycle exit, and (ii) they directly influence the transcriptional activity of genes that promote the differentiation process. The role of E2F4 in cell cycle control, differentiation and tumorigenesis will be investigated. The analysis of mouse embryonic fibroblasts will allow dissection of how the E2F4 complexes contribute to the regulation of E2F-responsive gene transcription, the induction of cell cycle exit and the inhibition of apoptosis. Whole animal and in vitro differentiation studies will be used to determine how E2F4 complexes participate in the differentiation process. Finally, through a combination of tumor analysis and biochemical studies, the mechanism by which E2F4-loss suppresses the development of pRB-deficient tumors will be determined. Preliminary studies suggest that this occurs through a novel mechanism that suggests alternative strategies for the design of chemotherapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM053204-09
Application #
6875676
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Zatz, Marion M
Project Start
1997-04-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
9
Fiscal Year
2005
Total Cost
$345,213
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Internal Medicine/Medicine
Type
Schools of Arts and Sciences
DUNS #
001425594
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Zhang, Jing; Lee, Eunice Y; Liu, Yangang et al. (2010) pRB and E2F4 play distinct cell-intrinsic roles in fetal erythropoiesis. Cell Cycle 9:371-6
Miller, Emily S; Berman, Seth D; Yuan, Tina L et al. (2010) Disruption of calvarial ossification in E2f4 mutant embryos correlates with increased proliferation and progenitor cell populations. Cell Cycle 9:2620-8
Lee, Eunice Y; Yuan, Tina L; Danielian, Paul S et al. (2009) E2F4 cooperates with pRB in the development of extra-embryonic tissues. Dev Biol 332:104-15
Berman, Seth D; Yuan, Tina L; Miller, Emily S et al. (2008) The retinoblastoma protein tumor suppressor is important for appropriate osteoblast differentiation and bone development. Mol Cancer Res 6:1440-51
Courel, Maria; Friesenhahn, Laurie; Lees, Jacqueline A (2008) E2f6 and Bmi1 cooperate in axial skeletal development. Dev Dyn 237:1232-42
Danielian, Paul S; Bender Kim, Carla F; Caron, Alicia M et al. (2007) E2f4 is required for normal development of the airway epithelium. Dev Biol 305:564-76
Parisi, Tiziana; Yuan, Tina L; Faust, Ann Marie et al. (2007) Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues. Mol Cell Biol 27:2283-93
Landsberg, Rebecca L; Sero, Julia E; Danielian, Paul S et al. (2003) The role of E2F4 in adipogenesis is independent of its cell cycle regulatory activity. Proc Natl Acad Sci U S A 100:2456-61
Fajas, Lluis; Landsberg, Rebecca L; Huss-Garcia, Yolande et al. (2002) E2Fs regulate adipocyte differentiation. Dev Cell 3:39-49