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.
| Amelio, Antonio L; Fallahi, Mohammad; Schaub, Franz X et al. (2014) CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement. Proc Natl Acad Sci U S A 111:E3260-8 |
| Doherty, Joanne R; Yang, Chunying; Scott, Kristen E N et al. (2014) Blocking lactate export by inhibiting the Myc target MCT1 Disables glycolysis and glutathione synthesis. Cancer Res 74:908-20 |
| Jablonski, Joseph A; Amelio, Antonio L; Giacca, Mauro et al. (2010) The transcriptional transactivator Tat selectively regulates viral splicing. Nucleic Acids Res 38:1249-60 |
| Hollander, Jonathan A; Im, Heh-In; Amelio, Antonio L et al. (2010) Striatal microRNA controls cocaine intake through CREB signalling. Nature 466:197-202 |
| Amelio, Antonio L; Caputi, Massimo; Conkright, Michael D (2009) Bipartite functions of the CREB co-activators selectively direct alternative splicing or transcriptional activation. EMBO J 28:2733-47 |
