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

描述(申请人提供)：该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)和沃辛瘤是一种唾液腺肿瘤，具有共同的t(11；19)(q21；p13.1)易位。尽管有这种常见的遗传异常，但每个肿瘤都表现出不同的致病特征，其中MEC是最常见的涎腺和支气管肿瘤，而沃辛瘤是第二常见的腮腺良性肿瘤。染色体重排通过融合TORC1(MECT1)和MAML2形成嵌合癌基因。因此，TORC1/MAML2易位诱导了许多基因的表达，这些基因分别是TORC1和MAML2的靶标CREB和Noch调控的。这些靶基因的放松被认为是导致肿瘤发生的原因。然而，MAX网络调节与细胞增殖、分化、凋亡和新陈代谢有关的基因，而这些基因在携带TORC1/MAML2易位的肿瘤中被解除调控。这是意想不到的，因为TORC1和MAML2都不知道与MAX复合体相互作用。到目前为止，MAX靶基因在TORC1/MAML2介导的肿瘤发生中的作用还没有被夸大。我们的研究表明，TORC1/MAML2嵌合体可以在功能荧光素酶屏幕上激活MAX，其中GAL4-MAX被拴在GAL4 UAS启动子上，但TORC1和MAML2亲本分子都没有显示这一活性。因此，这笔拨款的重点是阐明TORC1MAML2癌基因实现这种新的MAX相互作用的机制(S)以及MAX(和MYC)调节涎腺肿瘤发展的程度。具体目标1将表征TORC1/MAML2与MAX的相互作用，并表征由这种新的相互作用特异性诱导的基因子集。具体目标2将解决已确定的相互作用的生物学后果，在体外和体内的肿瘤发展模型。全面了解这种新的相互作用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。 2007年的统计数据显示，癌症是美国第二大死因。在553,888名死于癌症的患者中，31%和26%的男性患者和女性患者分别死于肺癌和支气管癌。产生TORC1/MAML2融合蛋白的染色体重排已被连接到支气管瘤的一个亚群，因此提出了一个重大的临床和科学挑战，需要详细的研究。

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.