The Aims of this proposal are to study the molecular mechanisms of transformation of melanocytic cells elicited by the ectopic expression of the G-protein-coupled seven transmembrane-domain receptor, Grm1, and to examine the requirement of continuing expression of Grm1in mediating its oncogenic potential in these cells.
Our Aims are based on our initial hypothesis and confirmation of the hypothesis in our recent publication. Previously we proposed to use a line of transgenic mice, TG-3, with a predisposition to spontaneous melanoma development as a model system to study this disease. We identified the altered host sequences due to the integration of the transgene to be Grm1. We showed the aberrant expression of Grm1 in tumor but not control samples. We hypothesized that Grm1 is responsible for the genesis of melanoma in TG- 3. We then tested this hypothesis by generating a new transgenic line with expression of Grm1l targeted only to melanocytes, by placing the cDNA of Grm1 under the regulation of the melanocyte specific promoter, dopachrome tautomerase (Dct). This new Dct-Grm1 transgenic line (the E line) showed predisposition to melanoma development similar to that of TG-3. Furthermore, we also demonstrated the expression of GRM1 in some human melanoma cell lines and biopsy samples but not in normal melanocytes or benign nevi. Thus, we have demonstrated unequivocally the etiological role of aberrant Grm1 expression and melanoma development in our system. Based on these results, we propose to initial a set of experiments using cells derived from melanocytic tumors to begin to unravel the complicated yet well coordinated network of cellular transformation using our model system.
Our specific aims are: 1. To investigate and characterize the requirement for continuing expression of Grm1l in the maintenance of the transformed phenotypes. 2. To extend and validate the oncogenic role of Grm1 in human melanoma. 3. To examine the requirement for continuous Grm1 expression in onset and progression of tumor in TG-3 mice. 4. To explore MAPK signaling in our mouse model system.
| Wall, Brian A; Yu, Lumeng J; Khan, Atif et al. (2015) Riluzole is a radio-sensitizing agent in an in vivo model of brain metastasis derived from GRM1 expressing human melanoma cells. Pigment Cell Melanoma Res 28:105-9 |
| Teh, Jessica L F; Shah, Raj; La Cava, Stephanie et al. (2015) Metabotropic glutamate receptor 1 disrupts mammary acinar architecture and initiates malignant transformation of mammary epithelial cells. Breast Cancer Res Treat 151:57-73 |
| Teh, Jessica L F; Shah, Raj; Shin, Seung-Shick et al. (2014) Metabotropic glutamate receptor 1 mediates melanocyte transformation via transactivation of insulin-like growth factor 1 receptor. Pigment Cell Melanoma Res 27:621-9 |
| Martino, J J; Wall, B A; Mastrantoni, E et al. (2013) Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells. Oncogene 32:4366-76 |
| Naczynski, D J; Tan, M C; Zevon, M et al. (2013) Rare-earth-doped biological composites as in vivo shortwave infrared reporters. Nat Commun 4:2199 |
| Wangari-Talbot, Janet; Wall, Brian A; Goydos, James S et al. (2012) Functional effects of GRM1 suppression in human melanoma cells. Mol Cancer Res 10:1440-50 |
| Teh, Jessica; Chen, Suzie (2012) mGlu Receptors and Cancerous Growth. Wiley Interdiscip Rev Membr Transp Signal 1:211-220 |
| Lee, Hwa Jin; Wall, Brian A; Wangari-Talbot, Janet et al. (2012) Regulation of mGluR1 expression in human melanocytes and melanoma cells. Biochim Biophys Acta 1819:1123-31 |
| Lee, Hwa Jin; Wall, Brian A; Wangari-Talbot, Janet et al. (2011) Glutamatergic pathway targeting in melanoma: single-agent and combinatorial therapies. Clin Cancer Res 17:7080-92 |
| Shin, Seung-Shick; Wall, Brian A; Goydos, James S et al. (2010) AKT2 is a downstream target of metabotropic glutamate receptor 1 (Grm1). Pigment Cell Melanoma Res 23:103-11 |
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