This is application proposing to determine whether failure to undergo programmed cell death contributes to the pathogenesis of human neuroblastoma. Specifically, the investigator proposes to determine whether oncogene products which modulate programmed cell death (PCD) influence whether oncogene products which modulate programmed cell death (PCD) influence the malignant phenotype of neuroblastoma. The investigator previously determined that Bcl-2, which suppresses PCD, is present in pretreatment neuroblastoma tumore biopsies, and that, when deregulated, inhibits neuroblastoma tumor biopsies, and that, when deregulated, inhibits chemotherapy-induced PCD in neuroblastoma. Based on these prior findings, the investigator seeks to extend these observations in a system in which it is proposed that neuroblastoma is a disease resulting from failed apoptosis.
The first aim will address the issue of oncogene cooperativity in the malignant phenotype of neuroblastoma,, specifically whether Bcl-2, in its capacity to inhibit apoptosis, cooperates with N-myc to transform cells.
The second aim i s proposed to determine whether Bcl-xs expression will lead to neuroblastoma cell death and enhanced response to chemotherapy (by pirating existing cell machinery). The third specific aim proposes to determine the expression of the death gene and survival gene in normal tissue from which neuroblastoma is thought to arise. The investigator feels these experiments will address the molecular link between the benign lesions and malignant neuroblastoma.
| Timakhov, Roman A; Tan, Yinfei; Rao, Mamta et al. (2009) Recurrent chromosomal rearrangements implicate oncogenes contributing to T-cell lymphomagenesis in Lck-MyrAkt2 transgenic mice. Genes Chromosomes Cancer 48:786-94 |
| Martin, Darryl T; Gendron, Robert L; Jarzembowski, Jason A et al. (2007) Tubedown expression correlates with the differentiation status and aggressiveness of neuroblastic tumors. Clin Cancer Res 13:1480-7 |
| Bian, Xin; Giordano, Thomas D; Lin, Huey-Jen et al. (2004) Chemotherapy-induced apoptosis of S-type neuroblastoma cells requires caspase-9 and is augmented by CD95/Fas stimulation. J Biol Chem 279:4663-9 |
| Bian, X; McAllister-Lucas, L M; Shao, F et al. (2001) NF-kappa B activation mediates doxorubicin-induced cell death in N-type neuroblastoma cells. J Biol Chem 276:48921-9 |
| van Golen, C M; Castle, V P; Feldman, E L (2000) IGF-I receptor activation and BCL-2 overexpression prevent early apoptotic events in human neuroblastoma. Cell Death Differ 7:654-65 |
