The human retinoblastoma gene (RB-1) is a well-established tumor suppressor. Somatic RB-1 inactivation is observed in approximately one third of all human tumors. Individuals carrying germline RB-1 mutations develop retinoblastoma with near complete penetrance and they are also highly predisposed to develop osteosarcomas. The retinoblastoma protein (pRB) inhibits cellular proliferation by binding to the E2F transcription factors and thereby blocks the activation of genes encoding essential components of the cell division machinery. pRB has also been shown to bind transcription factors that are master regulators of differentiation. Together, these observations suggest that pRB acts to coordinate cell cycle arrest and terminal differentiation. The analysis of mutant mouse models and cell lines has been used to gain insight into the roles of pRB and E2F4 in vivo. First, these studies show that E2F4-loss suppresses the development of pRB-deficient tumors. Molecular studies suggest a hypothesis for the underlying basis of E2F4's oncogenic activity. Experiments in aim 1 will directly test this hypothesis. Second, these studies show that pRB and E2F4 are required for the appropriate development of numerous tissues. In particular they reveal important roles for both pRB and E2F4 in the development of bone arising via either intramembranous or endochondral ossification. Experiments in aim 2 will continue to investigate the mechanisms by which pRB and E2F4 contribute to differentiation with particular emphasis on bone development.
In Aim 3, we will use osteoblast-specific Rb mouse models to further investigate pRB's role in osteogenesis and osteosarcoma formation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA121921-12
Application #
7390646
Study Section
Special Emphasis Panel (ZRG1-ONC-U (90))
Program Officer
Yassin, Rihab R,
Project Start
1997-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
12
Fiscal Year
2008
Total Cost
$319,945
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
Parisi, T; Bronson, R T; Lees, J A (2015) Inactivation of the retinoblastoma gene yields a mouse model of malignant colorectal cancer. Oncogene 34:5890-9
Landman, A S; Danielian, P S; Lees, J A (2013) Loss of pRB and p107 disrupts cartilage development and promotes enchondroma formation. Oncogene 32:4798-805
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
Calo, Eliezer; Quintero-Estades, Jose A; Danielian, Paul S et al. (2010) Rb regulates fate choice and lineage commitment in vivo. Nature 466:1110-4
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; West, Julie C; Danielian, Paul S et al. (2009) Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects. Proc Natl Acad Sci U S A 106:14932-6
Parisi, T; Bronson, R T; Lees, J A (2009) Inhibition of pituitary tumors in Rb mutant chimeras through E2f4 loss reveals a key suppressive role for the pRB/E2F pathway in urothelium and ganglionic carcinogenesis. Oncogene 28:500-8
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

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