Neoplastic transformation of melanocytes by Grm1

Grm1 对黑素细胞的肿瘤转化

• 批准号: 7406033
• 负责人: Suzie Chen
• 金额: $ 23.65万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406033
• 关键词: Agar; Agonist; Animal Model; Animals; Antigens; Apoptosis; Benign; Biological Assay; Biological Models; Biological Process; Biopsy; Biopsy Specimen; Cell Death; Cell Line; Cell membrane; Cells; Commit; Complementary DNA; Cutaneous; DNA; Data; Development; Disease; Dominant-Negative Mutation; Dopachrome isomerase; Dose; Ectopic Expression; Environment; Excitatory Amino Acids; Exhibits; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptors; Future; GRM1 gene; GTP-Binding Proteins; Genes; Genomics; Growth; Human; In Vitro; Injection of therapeutic agent; Lesion; Ligands; MEKs; Maintenance; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Melanocytic Neoplasm; Melanocytic nevus; Melanoma Cell; Methods; Mitogen-Activated Protein Kinases; Mitotic Cell Cycle; Molecular; Monitor; Mus; Mutation; Necrosis; Neoplastic Cell Transformation; Neuraxis; Nevus; Nude Mice; Numbers; Oncogenes; Oncogenic; Phenotype; Pigments; Play; Predisposition; Property; Publications; RNA Interference; Ras/Raf; Regulation; Reporting; Research Personnel; Role; Sampling; Signal Transduction; Solid; Specificity; System; Testing; Tetanus Helper Peptide; Thinking; Time; Tissue Sample; Transfection; Transgenes; Transgenic Mice; Transgenic Organisms; Transmembrane Domain; Tumor Volume; Tumorigenicity; adipocyte differentiation; base; cell growth; cell transformation; in vivo; melanocyte; melanoma; member; metabotropic glutamate receptor type 1; metaplastic cell transformation; monolayer; mouse model; neoplastic cell; neurotransmission; programs; promoter; receptor; research study; therapeutic target; tool; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic; Agar; Agonist; Animal Model; Animals; Antigens; Apoptosis; Benign; Biological Assay; Biological Models; Biological Process; Biopsy; Biopsy Specimen; Cell Death; Cell Line; Cell membrane; Cells; Commit; Complementary DNA; Cutaneous; DNA; Data; Development; Disease; Dominant-Negative Mutation; Dopachrome isomerase; Dose; Ectopic Expression; Environment; Excitatory Amino Acids; Exhibits; Fibroblast Growth Factor 2; Fibroblast Growth Factor Receptors; Future; GRM1 gene; GTP-Binding Proteins; Genes; Genomics; Growth; Human; In Vitro; Injection of therapeutic agent; Lesion; Ligands; MEKs; Maintenance; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Melanocytic Neoplasm; Melanocytic nevus; Melanoma Cell; Methods; Mitogen-Activated Protein Kinases; Mitotic Cell Cycle; Molecular; Monitor; Mus; Mutation; Necrosis; Neoplastic Cell Transformation; Neuraxis; Nevus; Nude Mice; Numbers; Oncogenes; Oncogenic; Phenotype; Pigments; Play; Predisposition; Property; Publications; RNA Interference; Ras/Raf; Regulation; Reporting; Research Personnel; Role; Sampling; Signal Transduction; Solid; Specificity; System; Testing; Tetanus Helper Peptide; Thinking; Time; Tissue Sample; Transfection; Transgenes; Transgenic Mice; Transgenic Organisms; Transmembrane Domain; Tumor Volume; Tumorigenicity; adipocyte differentiation; base; cell growth; cell transformation; in vivo; melanocyte; melanoma; member; metabotropic glutamate receptor type 1; metaplastic cell transformation; monolayer; mouse model; neoplastic cell; neurotransmission; programs; promoter; receptor; research study; therapeutic target; tool; tumor; tumor growth; tumor progression; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：该提案的目的是研究通过G蛋白偶联的七个跨膜膜受体GRM1的异位表达引起的黑素细胞细胞转化的分子机制，并检查连续介导GRM1In介导其在这些细胞中的表达的需求。我们的目标是基于我们最初的假设和对我们最近出版的假设的确认。以前，我们建议使用一系列转基因小鼠TG-3，倾向于自发黑色素瘤作为研究这种疾病的模型系统。由于转基因的整合为GRM1，我们确定了改变的主机序列。我们显示了GRM1在肿瘤中的异常表达，但没有对照样品。我们假设GRM1负责TG-3中的黑色素瘤的发生。然后，我们通过将GRM1的表达仅针对黑色素细胞的表达而产生新的转基因线，通过将GRM1的cDNA放置在黑色素特异性启动子dopachrome，Dopachrome dopachrome dopachrome，dopachrome dopachrome tautomerasase（dct）中。这种新的DCT-GRM1转基因线（E系）表现出与TG-3相似的黑色素瘤发育倾向。此外，我们还证明了在某些人黑色素瘤细胞系和活检样品中GRM1的表达，但在正常的黑色素细胞或良性NEVI中没有表达。因此，我们明确地证明了异常GRM1表达和黑色素瘤在系统中的病因作用。基于这些结果，我们建议使用源自黑色素细胞肿瘤的细胞开始初始化一组实验，以开始使用我们的模型系统揭示复杂但良好的细胞转化网络。我们的具体目的是：1。调查并表征在维持转化表型中继续表达GRM1L的要求。 2。扩展和验证GRM1在人黑色素瘤中的致癌作用。 3。检查TG-3小鼠肿瘤发作和肿瘤进展中连续GRM1表达的要求。 4。在我们的鼠标模型系统中探索MAPK信号。