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

描述（由申请人提供）：该项目的长期目标是确定唾液腺肿瘤发展的分子机制。黏液表皮样癌（muco表皮样癌，MEC）和Warthin肿瘤是具有共同t(11;19)（q21;p13.1）易位的唾液腺肿瘤。尽管存在这种常见的遗传异常，但每种肿瘤都表现出不同的致病特征，其中MECs代表最常见的恶性唾液腺和支气管肿瘤，而Warthin肿瘤代表第二常见的良性腮腺肿瘤。染色体重排通过将TORC1 （MECT1）与MAML2融合形成嵌合癌基因。因此，TORC1/MAML2易位诱导了许多受CREB和NOTCH调控的基因的表达，CREB和NOTCH分别是TORC1和MAML2的靶点。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，这些基因已知在具有TORC1/MAML2易位的肿瘤中不受调控。这是出乎意料的，因为TORC1和MAML2都不与MAX复合物相互作用。迄今为止，MAX靶基因在TORC1/MAML2介导的肿瘤发生中的作用尚未得到解决。我们的研究表明，TORC1/MAML2嵌合体可以在功能性荧光素酶筛选中激活MAX，其中GAL4-MAX连接到GAL4 UAS启动子上，但TORC1和MAML2亲本分子都没有表现出这种活性。因此，本基金的重点是阐明TORC1/MAML2致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。Specific Aim 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异性诱导的基因子集。特异性目标2将讨论在离体和体内肿瘤发展模型中确定的相互作用的生物学后果。对这种新型相互作用的全面理解可能有助于解释唾液腺肿瘤中观察到的不同致病结果，并有助于这些癌症的诊断和治疗。

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.