The long-term objective of this work is to understand the role of Id2 (Inhibitor of differentiation-2) in controlling mammalian cell cycle progression and oncogenesis. Id2 is a member of the Helix-Loop-Helix (HLH) protein family initiated identified because of the ability to inhibit differentiation in different cell types. Id2 shares this property with other members of the Id family. However, increasing evidence points to a specific role of Id2 in promoting cell cycle progression. Only Id2 but not Id1 or Id3 can physically associated with the product of the retinoblastoma gene (pRb) and related proteins p107 and p130 (the """"""""pocket proteins"""""""") with the product of the retinoblastoma gene (pRb) and related proteins p107 and p130 (the """"""""pocket proteins"""""""") and abolish their ability to restrain growth. Also, only Id2 can overcome the block of cell proliferation imposed by the cyclin-dependent kinase inhibitor p16 Ink4A. The currently accepted model of mammalian cell cycle progression in G1 involves sequential phosphorylation of pocket proteins by cyclin D/cd4-6 and cyclin E/cdk2. A key question is how mitogenic extracellular signals are linked to initiation of G1 progression. The strict control of Id2 expression by extracellular signals coupled with its ability to stimulate cell cycle progression through interaction with hypophosphorylated, active proteins suggest that it could serve to promoter early cell cycle events. Perhaps consistent with this hypothesis, we recently found that early response genes of the Myc family of transcription factors activate expression of Id2. Proteins of the Myc family are probably the most frequently activated oncoproteins in human cancer. A role of Id2 as a target of Myc oncogenesis is proposed by specific over-expression of Id2 in neuroblastoma, a pediatric cancer carrying amplification of the oncogene N-myc.
The specific aims of this proposal will be to map the pathway that leads to activation of Id2 and induction of cell proliferation by: 1) characterizing the Id2 promoter/enhancer with respect to its responsiveness to Myc using an antisense strategy in cells engineered to express activated Myc and in neuroblastoma cells carrying amplification of N-myc; 2) identifying specific cell cycle-regulated events elicited by activation of Id2 in G0 by determining mechanisms of Id2-induced release of transcriptional repression of E2F by pocket proteins and the role of novel cellular partners of Id2; 3) determining the oncogenic role of Id2 as a target of N- Myc and as a new component of the pRb pathway in human neuroblastoma by immunohistochemical evaluation of primary tumor tissue specimens.
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| 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 |
| Coma, Silvia; Amin, Dhara N; Shimizu, Akio et al. (2010) Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer Res 70:3823-32 |
| D'Arca, Domenico; Zhao, Xudong; Xu, Wenming et al. (2010) Huwe1 ubiquitin ligase is essential to synchronize neuronal and glial differentiation in the developing cerebellum. Proc Natl Acad Sci U S A 107:5875-80 |
| Carro, Maria Stella; Lim, Wei Keat; Alvarez, Mariano Javier et al. (2010) The transcriptional network for mesenchymal transformation of brain tumours. Nature 463:318-25 |
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