Collaborating Mutations in Medulloblastoma

髓母细胞瘤中的协同突变

• 批准号: 8056131
• 负责人: MARTINE F. ROUSSEL (SHERR)
• 金额: $ 31.58万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8056131
• 关键词: Affect; Anaplastic Cell; Cell Cycle; Cerebellum; Child; Cyclin D1; Defect; Development; Disease; Down-Regulation; Engineering; Erinaceidae; Fostering; Frequencies; Gene Dosage; Gene Expression; Gene Mutation; Genes; Genetic; Human; Lead; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Methods; MicroRNAs; Mitogens; Molecular; Molecular Profiling; Mouse Strains; Mus; Mutation; Neurocognitive; Neuronal Differentiation; Oncogene Proteins; Operative Surgical Procedures; Other Genetics; Patients; Pediatric Neoplasm; Protein p53; Proteins; RNA; Radiation therapy; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; TP53 gene; Tumor Suppressor Proteins; Work; bone morphogenic protein; chemotherapy; improved; kinase inhibitor; loss of function; medulloblastoma; mouse model; novel; transcription factor; tumor

Medulloblastoma (MB) is the most common malignant brain tumor in children. MB is thought to arise from progenitor cells in the developing cerebellum that fail to exit the cell division cycle properly, thus providing fertile ground for tumor formation. Many genetic anomalies have been identified in human MB, but only a few have been revealed to be causative. We have genetically engineered two different MB-prone mouse strains that lack the cyclin-D-dependent kinase inhibitor, p18lnk4c, a cell cycle regulatory and tumor suppressor protein whose expression was also revealed to be reduced or absent in human MBs. In Specific Aim 1, we propose to document the frequency of inactivation of INK4C/CDKN2C in human MBs and to correlate its loss-of-function with other genetic mutations, gene copy number alterations, and gene expression profiles that define different human MB subsets. We will also explore the combined roles of the C-MYC oncoprotein and p53 tumor suppressor in generating a mouse model of large cell anaplastic MBs, the most aggressive and treatment-resistant form of the disease. Many mouse MBs are characterized by mutations affecting a signaling pathway dominated by the mitogen, Sonic Hedgehog (Shh); genetic alterations affecting the Shh signaling pathway have similarly been documented in a subset of human MBs. Our work has established a role for the bone morphogenic proteins (BMPs) in countering Shh signaling, thereby inhibiting proliferation of mouse MBs, and fostering their neuronal differentiation. Not only do BMPs strongly antagonize MB formation in our mouse models, but downregulation of many BMP-responsive genes is a hallmark of Shh-driven human tumors. In Specific Aim 2, we will study Mathl, a key transcription factor regulated by BMP signaling in an'effort to discern how the activity of this protein is governed, what genes it regulates, and why its role is seemingly essential for MB development. Finally, it is now widely appreciated that small regulatory RNA species (micro-RNAs) globally regulate gene expression and thereby contribute to many forms of cancer. In Specific Aim 3, we propose methods to characterize in detail the micro-RNAs that contribute to MB formation and tumor maintenance in both mice and humans.

髓母细胞瘤是儿童最常见的恶性脑肿瘤。MB被认为是由 小脑发育中的祖细胞不能正常退出细胞分裂周期，从而提供 是肿瘤形成的沃土在人类MB中已经发现了许多遗传异常，但只有一个 很少有人被证明是致病的。我们通过基因工程改造了两种不同的MB易感小鼠， 缺乏细胞周期蛋白D依赖性激酶抑制剂p18 lnk 4c的菌株，p18 lnk 4c是一种细胞周期调节和肿瘤抑制剂， 抑制蛋白，其表达在人MB中也被揭示为减少或缺失。在特定 目的1，我们建议记录人MB中INK 4C/CDKN 2C失活的频率， 将其功能丧失与其他基因突变、基因拷贝数改变和基因突变相关联。 定义不同人MB亚群的表达谱。我们还将探讨 C-MYC癌蛋白和p53肿瘤抑制因子在产生大细胞间变性MB小鼠模型中的作用， 最具侵略性和治疗抗性的疾病形式。许多小鼠MB的特征在于： 影响由有丝分裂原Sonic Hedgehog（Shh）主导的信号通路的突变;遗传 影响Shh信号通路的改变在人MB亚组中也有类似的记载。 我们的工作已经确定了骨形态发生蛋白（BMP）在对抗Shh信号传导中的作用， 从而抑制小鼠MB的增殖并促进其神经元分化。不仅BMP 在我们的小鼠模型中强烈拮抗MB的形成，但许多BMP反应基因的下调 是嘘驱动的人类肿瘤的标志。在具体目标2中，我们将研究Mathl，一个关键的转录因子 通过BMP信号调节，试图辨别这种蛋白质的活性是如何控制的， 环境署的作用似乎对甲基溴的发展至关重要。最后，现在人们普遍认为， 小的调节RNA种类（micro-RNA）全面调节基因表达，从而有助于 多种形式的癌症在具体目标3中，我们提出了详细描述微RNA的方法， 在小鼠和人类中，促进MB形成和肿瘤维持。