In mammalian cells, the Retinoblastoma (Rb) tumor suppressor protein is essential to execute terminal cell cycle withdrawal, complete differentiation and secure cell survival. In the absence of Rb, mouse development is impaired and Rb-mutant embryos die at mid-gestation with severe defects in erythropoiesis and neurogenesis. The helix-loop helix protein Inhibitor of differentiation 2 (Id2) coordinates proliferation and differentiation. Id2 binds Rb and antagonizes its antiproliferative function. We have recently reported that ablation of the mouse Id2 gene rescues the phenotypic abnormalities and lethality of Rb-mutant embryos. These results have identified Id2 as a relevant target of tumor suppressor proteins, whose function must be restrained by Rb during development. The long-term goal of this work is to understand the role of Rb-Id2 complexes in proliferation, differentiation and tumorigenesis using genetically modified mouse models. We have found that Rb is essential for differentiation of the macrophage/dendritic cell lineage, a cell type required to support erythropoiesis in the fetal liver. This is an exciting novel finding that will allow us to dissect the most relevant Rb-null defect, in order to trace the molecular events directed by the Rb-Id2 pathway in erythropoiesis. We will also determine the target specificity of Id2 in cell proliferation and differentiation by discriminating Id2 and E2F functions in the absence of Rb. Finally, to establish the role of Id2 in tumorigenesis initiated by inactivation of Rb, we will use a mouse model in which mutation of Rb predisposes to pituitary cancer. These experiments will increase our understanding of the mechanisms by which Rb promotes cell cycle arrest and differentiation in normal cells and the perturbation of these mechanisms in cellular transformation. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA101644-02
Application #
6782355
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Mietz, Judy
Project Start
2003-06-01
Project End
2008-05-31
Budget Start
2003-06-03
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$363,788
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Frattini, VĂ©ronique; Pagnotta, Stefano M; Tala et al. (2018) A metabolic function of FGFR3-TACC3 gene fusions in cancer. Nature 553:222-227
Wang, Jiguang; Cazzato, Emanuela; Ladewig, Erik et al. (2016) Clonal evolution of glioblastoma under therapy. Nat Genet 48:768-76
Lee, Sang Bae; Frattini, Veronique; Bansal, Mukesh et al. (2016) An ID2-dependent mechanism for VHL inactivation in cancer. Nature 529:172-7
Di Stefano, Anna Luisa; Fucci, Alessandra; Frattini, Veronique et al. (2015) Detection, Characterization, and Inhibition of FGFR-TACC Fusions in IDH Wild-type Glioma. Clin Cancer Res 21:3307-17
Iavarone, Antonio; Lasorella, Anna (2014) Myc and differentiation: going against the current. EMBO Rep 15:324-5
Frattini, Veronique; Trifonov, Vladimir; Chan, Joseph Minhow et al. (2013) The integrated landscape of driver genomic alterations in glioblastoma. Nat Genet 45:1141-9
Danussi, Carla; Akavia, Uri David; Niola, Francesco et al. (2013) RHPN2 drives mesenchymal transformation in malignant glioma by triggering RhoA activation. Cancer Res 73:5140-50
Niola, Francesco; Zhao, Xudong; Singh, Devendra et al. (2013) Mesenchymal high-grade glioma is maintained by the ID-RAP1 axis. J Clin Invest 123:405-17
Niola, Francesco; Zhao, Xudong; Singh, Devendra et al. (2012) Id proteins synchronize stemness and anchorage to the niche of neural stem cells. Nat Cell Biol 14:477-87
Singh, Devendra; Chan, Joseph Minhow; Zoppoli, Pietro et al. (2012) Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 337:1231-5

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