clear cell Renal Cell Carcinoma (cRCC) account for greater than 90% of Kidney-related malignancies. Our long-term goal is to elucidate cellular factors governing cRCC growth and metastasis as a prerequisite to development of therapeutic intervention protocols capable of alleviating the disease. There are two complimentary objectives of this proposal, namely (i) to elucidate the role of cell surface (CS) and secreted proteins (SP) in kidney tumor growth and metastasis, and (ii) to provide a mechanistic insight into a novel CS and SP accumulation phenotype.
The specific aims of the project will test the hypothesis that CS and SP molecules facilitate progression of human cRCC, a kidney cancer type arising from Von Hippel Lindau (VHL) gene mutations. The hypothesis is related to the published study identifying a central role for VHL in dynamin-dependent endocytosis. In further investigating its implications, a novel CS and SP accumulation phenotype was uncovered in VHL -/- cells that is consistent with failure of VHL-mediated dynamin-dependent pathways. The project has four main experimental foci (i) to establish the identity of CS and SP accumulated in cRCC by proteomic analysis, (ii) to provide a mechanistic understanding of the observed CS and SP phenotype, (iii) to study role of the identified CS and SP in cRCC disease process, and (iv) use the knowledge gained for diagnostics and tumor-specific delivery of therapeutic agents. Together these experiments will elucidate cellular mechanisms influencing cRCC biology and their potential applications in diagnosis and treatment. Relevance: The current proposal addresses important aspects of the mechanisms of VHL-related kidney disease that should lead to immediate therapies and future discovery of novel mechanisms of tumorigenesis. ? ? ? ?
|Hsouna, Anita; Nallamothu, Gouthami; Kose, Nurgun et al. (2010) Drosophila von Hippel-Lindau tumor suppressor gene function in epithelial tubule morphogenesis. Mol Cell Biol 30:3779-94|
|Dammai, Vincent (2010) A rapid and versatile PCR-based site-directed mutagenesis protocol for generation of mutations along the entire length of a cloned cDNA. Methods Mol Biol 634:111-26|
|Nallamothu, Gouthami; Dammai, Vincent; Hsu, Tien (2009) Developmental function of Nm23/awd: a mediator of endocytosis. Mol Cell Biochem 329:35-44|
|Nallamothu, Gouthami; Woolworth, Julie A; Dammai, Vincent et al. (2008) Awd, the homolog of metastasis suppressor gene Nm23, regulates Drosophila epithelial cell invasion. Mol Cell Biol 28:1964-73|
|Mahajan, S; Dammai, V; Hsu, T et al. (2008) Hypoxia-inducible factor-2alpha regulates the expression of TRAIL receptor DR5 in renal cancer cells. Carcinogenesis 29:1734-41|
|Champion, Kristen J; Guinea, Maria; Dammai, Vincent et al. (2008) Endothelial function of von Hippel-Lindau tumor suppressor gene: control of fibroblast growth factor receptor signaling. Cancer Res 68:4649-57|
|Chintalapudi, Mastan R; Markiewicz, Margaret; Kose, Nurgun et al. (2008) Cyr61/CCN1 and CTGF/CCN2 mediate the proangiogenic activity of VHL-mutant renal carcinoma cells. Carcinogenesis 29:696-703|