The Role of MCM7 in Neuroblastoma Tumorigenesis

MCM7 在神经母细胞瘤肿瘤发生中的作用

• 批准号: 7078552
• 负责人: JASON M SHOHET
• 金额: $ 13.4万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7078552
• 关键词: DNA binding protein; DNA replication; carcinogenesis; flow cytometry; fluorescent in situ hybridization; gene expression; gene expression profiling; genetic transcription; genetically modified animals; histology; immunocytochemistry; laboratory mouse; neoplasm /cancer genetics; neuroblastoma; oncogenes; pediatric neoplasm /cancer; plasminogen activator; polymerase chain reaction; protein protein interaction; protein structure function; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）： 神经母细胞瘤是儿童中最常见的颅外实体瘤，尽管现代剂量密集化疗，但仍占所有儿科癌症死亡的15%。 治疗的改进将来自对这种癌症生物学的更深入理解。 临床和生物学风险分层将MYCN癌基因确定为高危疾病的唯一可靠标志物。 MYCN在25-35%的病例中扩增，并区分具有高度侵袭性疾病和预后不良的患者子集。 MYCN蛋白是一种bHLH亮氨酸拉链核蛋白，其与MAX蛋白形成异二聚体并结合DNA，同时充当转录激活因子和阻遏物。 然而，MYCN的直接下游目标连接其过度表达，特别是恶性表型仍然不确定。 利用基因表达谱分析和消减杂交技术，我们已经确定了一系列MYCN调控基因。 这些基因之一，MCM 7是这个建议的重点。 MCM 7是MYCN的直接转录靶点，在S期调控DNA复制具有重要功能。 该基因与几种重要的调控分子相互作用，包括Rb和MAT 1激酶。 我们已经表明，MCM 7的表达密切相关的MYCN在体内扩增，它改变了细胞培养系统中的基因转录。 该建议的中心假设是，MCM 7的异常表达介导至少一些MYCN癌基因扩增的转化和恶性后果，通过改变DNA合成过程，诱导染色体不稳定性，或通过其与其他非MCM蛋白的相互作用介导的基因转录的继发性变化。 本提案的具体目标将追求这一假设，并测试MCM 7是否是新的治疗干预的良好靶标，如下：具体目标I将测试MCM 7功能的抑制是否会影响神经母细胞瘤细胞系的生长和转移。 特异性目的II将表征由MCM 7过表达诱导的染色体不稳定性的机制和特异性。 具体目标III将评估具有组织特异性组成型MCM 7过表达的转基因小鼠中的表型变化和肿瘤发生率。

项目成果

G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy-resistant or relapsed tumors and are highly tumorigenic.

• DOI: 10.1158/0008-5472.can-12-4056
• 发表时间: 2013-07-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Hsu DM;Agarwal S;Benham A;Coarfa C;Trahan DN;Chen Z;Stowers PN;Courtney AN;Lakoma A;Barbieri E;Metelitsa LS;Gunaratne P;Kim ES;Shohet JM
• 通讯作者: Shohet JM

MYCN-directed centrosome amplification requires MDM2-mediated suppression of p53 activity in neuroblastoma cells.

• DOI: 10.1158/0008-5472.can-06-1661
• 发表时间: 2007-03
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: A. Slack;Zaowen Chen;A. Ludwig;J. Hicks;J. Shohet