Neuroblastoma is the most common extra-cranial solid tumor in children, accounting for 15% of all pediatric cancer deaths despite modern dose-intensive chemotherapy. Improvements in therapy will come from a deeper understanding of the biology of this cancer. Clinical and biological risk stratification identifies the MYCN oncogene as the sole reliable marker for high-risk disease. MYCN is amplified in 25-35% of cases and distinguishes a subset of patients with highly aggressive disease and poor prognosis. The MYCN protein is a bHLH leucine zipper nuclear protein that forms heterodimers with the MAX protein and binds to DNA acting as both a transcriptional activator and repressor. However, direct downstream targets of MYCN connecting its overexpression to the particularly malignant phenotype remain undefined. Using gene expression profiling and subtractive hybridization we have identified a series of MYCN regulated genes. One of these genes, MCM7 is the focus of this proposal. MCM7 is a direct transcriptional target of MYCN with essential functions regulation DNA replication in S-phase. This gene interacts with several important regulatory molecules including Rb and MAT1 kinase. We have shown that MCM7 expression closely correlates with MYCN amplification in vivo and that it alters gene transcription in a cell culture system. The central hypothesis of this proposal is that aberrant expression of MCM7 mediates at least some of the transformative and malignant consequences of MYCN oncogene amplification through alterations in DNA synthetic processes, induction of chromosomal instability, or secondary changes in gene transcription mediated by its interaction with other non-MCM proteins.
The specific aims of this proposal will pursue this hypothesis and test whether MCM7 is a good target for novel therapeutic interventions as follows:
Specific Aim I will test whether inhibition of MCM7 function will influence the growth and metastasis of neuroblastoma cell lines.
Specific Aim II will characterize the mechanism and specificity of chromosomal instability induced by overexpression of MCM7.
Specific Aim III will evaluate phenotypic changes and tumor incidence in transgenic mice with tissue specific constitutive overexpression of MCM7. ? ?
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| Slack, Andrew D; Chen, Zaowen; Ludwig, Andrew D et al. (2007) MYCN-directed centrosome amplification requires MDM2-mediated suppression of p53 activity in neuroblastoma cells. Cancer Res 67:2448-55 |
| Honeycutt, K A; Chen, Z; Koster, M I et al. (2006) Deregulated minichromosomal maintenance protein MCM7 contributes to oncogene driven tumorigenesis. Oncogene 25:4027-32 |
| Barbieri, Eveline; Mehta, Parth; Chen, Zaowen et al. (2006) MDM2 inhibition sensitizes neuroblastoma to chemotherapy-induced apoptotic cell death. Mol Cancer Ther 5:2358-65 |
| Slack, Andrew; Chen, Zaowen; Tonelli, Roberto et al. (2005) The p53 regulatory gene MDM2 is a direct transcriptional target of MYCN in neuroblastoma. Proc Natl Acad Sci U S A 102:731-6 |
