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）：该项目的长期目标是定义控制唾液腺肿瘤发展的分子机制。粘膜表皮类癌（MEC）和Warthin的肿瘤是唾液腺肿瘤，共有t（11; 19）（q21; p13.1）易位。尽管存在这种常见的遗传异常，但每个肿瘤都表现出不同的致病性状，MEC代表最常见的恶性唾液腺和支气管肿瘤，而沃思素的肿瘤则代表了第二个最常见的良性良性腮腺肿瘤。染色体重排将TORC1（MECT1）与MAML2融合而形成嵌合癌基因。因此，TORC1/MAML2易位分别诱导由CREB和NOTCH调节的许多基因的表达，分别是TORC1和MAML2的靶标。这些靶基因的放松管制被认为会导致肿瘤发生。然而，最大网络调节与细胞增殖，分化，凋亡和代谢有关的基因，并且已知这些基因在带有TORC1/MAML2易位的肿瘤中受管制。鉴于TORC1和MAML2都不知道与最大配合物相互作用，这是出乎意料的。迄今为止，尚未添加最大靶基因在TORC1/MAML2介导的肿瘤发生中的贡献。我们的研究表明，TORC1/MAML2嵌合体可以在功能性的荧光素酶筛选中激活Max，其中GAL4-MAX将GAL4-MAX束缚在GAL4 UAS启动子上，但是Torc1和Maml2 Parents barts Molecule均未对此活性进行外交。因此，该赠款的重点是阐明TORC1/MAML2致癌基因实现这种新型最大相互作用以及Max（Max和Myc）调节唾液腺肿瘤发展的程度的机制。特定的目标1将表征Torc1/MAML2与MAX的相互作用，并表征由这种新型相互作用特别诱导的基因的子集。特定的目标2将解决离体和体内肿瘤发育模型内确定相互作用的生物学后果。对这种新型相互作用的全面了解可能有助于解释唾液腺肿瘤中观察到的不同致病结果，并有助于诊断和治疗这些癌症。 当前的2007年统计数据表明，癌症是美国第二大死亡原因。在癌症导致的553,888例死亡中，有31％和26％是由于男性和女性患者的肺和支气管癌。产生TORC1/MAML2融合蛋白的染色体重排已与支气管肿瘤的一部分有关，因此提出了重大的临床和科学挑战，需要详细研究。