Characterizing the Role of MYC-MAX Complexes in TORC1/MAML2-mediated Oncogenesis

表征 MYC-MAX 复合物在 TORC1/MAML2 介导的肿瘤发生中的作用

• 批准号: 7540099
• 负责人: Antonio Luigi Amelio
• 金额: $ 4.96万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540099
• 关键词: Address; Adenolymphoma; Affect; Apoptosis; Benign; Biological; Biological Assay; Bronchi; CREB1 gene; Cause of Death; Cell Proliferation; Cells; Cessation of life; Characteristics; Chimera organism; Chimeric Proteins; Chromosomal Rearrangement; Chromosomal translocation; Clinical; Co-Immunoprecipitations; Complex; Cyclic AMP; DNA Binding; Development; Diagnosis; Dimerization; Electrophoretic Mobility Shift Assay; Female; Gene Targeting; Genes; Genetic; Goals; Grant; Hand; Human; Investigation; Link; Luciferases; Lung; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolism; Molecular; Mucoepidermoid Carcinoma; Mus; Notch Signaling Pathway; Oncogene Deregulation; Oncogene Proteins; Oncogenes; Outcome; Parents; Parotid Neoplasms; Patients; Play; Property; Protein Overexpression; Proteins; Reporting; Research Project Grants; Role; Salivary Gland Neoplasms; Salivary Glands; Second Primary Cancers; Signal Pathway; Site-Directed Mutagenesis; Testing; Transcription Coactivator; Transcriptional Activation; Transducers; United States; Xenograft Model; cancer therapy; chromatin immunoprecipitation; in vivo; in vivo Model; male; notch protein; novel; promoter; research study; statistics; trait; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): The long-term goal of this project is to define the molecular mechanisms that govern the development of salivary gland tumors. Mucoepidermoid carcinomas (MEC) and Warthin's tumors are salivary gland tumors that share a common t(11;19)(q21;p13.1) translocation. Despite this common genetic anomaly, each tumor displays distinct pathogenic traits with MECs representing the most common malignant salivary gland and bronchial tumors while Warthin's tumors represent the second most common benign parotid gland tumor. The chromosomal rearrangement forms a chimeric oncogene by fusing TORC1 (MECT1) to MAML2. Consequently, the TORC1/MAML2 translocation induces the expression of many genes regulated by CREB and NOTCH, targets of TORC1 and MAML2, respectively. The deregulation of these target genes is believed to cause tumorigenesis. The MAX network, however, regulates genes involved in cell proliferation, differentiation, apoptosis, and metabolism and these genes are known to be deregulated in tumors harboring the TORC1/MAML2 translocation. This is unexpected given that neither TORC1 nor MAML2 are known to interact with MAX complexes. To date, the contribution of MAX target genes in TORC1/MAML2- mediated tumorigenesis has not been adddressed. Our studies have shown that the TORC1/MAML2 chimera can activate MAX in a functional luciferase screen where GAL4-MAX is tethered to a GAL4 UAS promoter, but neither TORC1 nor MAML2 parent molecule diplayed this activity. Therefore, this grant focuses on elucidating the mechanism(s) by which the TORC1/MAML2 oncogene achieves this novel MAX interaction and the extent to which MAX (and MYC) regulate salivary gland tumor development. Specific Aim 1 will characterize the interaction of TORC1/MAML2 with MAX and characterize a subset of genes specifically induced by this novel interaction. Specific Aim 2 will address the biological consequece of the identified interaction within ex vivo and in vivo models of tumor development. A comprehensive understanding of this novel interaction may help explain disparate pathogenic outcomes observed in salivary gland tumors and assist in the diagnosis and treatment of these cancers. Current 2007 statistics reveal that cancers are the second leading cause of death in the United States. Of the 553,888 deaths due to cancer, 31% and 26% are due to lung and bronchus cancers in male and female patients respectively. The chromosomal rearrangement that produces the TORC1/MAML2 fusion protein has been linked to a subset of bronchial tumors, and therefore presents a significant clinical and scientific challenge that requires detailed investigation.

描述（由申请人提供）：本项目的长期目标是确定控制唾液腺肿瘤发展的分子机制。粘液表皮样癌（MEC）和沃辛肿瘤是唾液腺肿瘤，共有一个共同的t（11;19）（q21;p13.1）易位。尽管有这种常见的遗传异常，但每种肿瘤都显示出不同的致病特征，MEC代表最常见的恶性唾液腺和支气管肿瘤，而沃辛瘤代表第二常见的良性腮腺肿瘤。染色体重排通过将TORC 1（MECT 1）融合到MAML 2上形成嵌合癌基因。因此，TORC 1/MAML 2易位诱导了许多受CREB和NOTCH调节的基因的表达，CREB和NOTCH分别是TORC 1和MAML 2的靶标。这些靶基因的失调被认为是导致肿瘤发生的原因。然而，MAX网络调节参与细胞增殖、分化、凋亡和代谢的基因，并且已知这些基因在携带TORC 1/MAML 2易位的肿瘤中被失调。这是出乎意料的，因为已知TORC 1和MAML 2都不与MAX复合物相互作用。迄今为止，MAX靶基因在TORC 1/MAML 2介导的肿瘤发生中的作用尚未得到解决。我们的研究表明，TORC 1/MAML 2嵌合体可以在功能性荧光素酶筛选中激活MAX，其中GAL 4-MAX与GAL 4 UAS启动子相连，但TORC 1和MAML 2亲本分子都不显示这种活性。因此，这项资助的重点是阐明TORC 1/MAML 2癌基因实现这种新型MAX相互作用的机制以及MAX（和MYC）调节唾液腺肿瘤发展的程度。具体目标1将表征TORC 1/MAML 2与MAX的相互作用，并表征由这种新型相互作用特异性诱导的基因子集。具体目标2将解决在肿瘤发展的离体和体内模型中确定的相互作用的生物学后果。对这种新的相互作用的全面理解可能有助于解释在唾液腺肿瘤中观察到的不同的致病结果，并有助于这些癌症的诊断和治疗。 目前2007年的统计数据显示，癌症是美国第二大死亡原因。在553，888例癌症死亡中，男性和女性分别有31%和26%死于肺癌和支气管癌。产生TORC 1/MAML 2融合蛋白的染色体重排与支气管肿瘤的一个子集有关，因此提出了一个重要的临床和科学挑战，需要详细的研究。