Angiogenesis plays a pivotal role in several important pathological disease processes as well as in normal physiology. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefits. Like many human carcinomas, renal cell carcinomas (RCC), which are characteristically highly vascular, are thought to induce angiogenesis by secreting an angiogenic cytokine: vascular permeability factor, also known as vascular endothelial growth factor (VPF/VEGF). The long-term goal of this proposal is to investigate in depth the regulatory role of VPF/VEGF in RCC. RCC, arising sporadically or in the von Hippel Lindau (VHL) syndrome, exhibits loss of function of a tumor suppressor gene, VHL. Previously, our laboratory as well as others have shown that wild type VHL (pVHL) selectively interacts with and thereby down-regulates the activities of PKCzeta and Sp-1 and also degrades alpha subunits of hypoxia inducible factors (HIFs); when pVHL is afunctional, as in RCC, VPF/VEGF is over-expressed. But the mechanism of VPF/VEGF over-expression in the absence of pVHL is not yet clear.
In Aim 1, we will study how PKC zeta interplays with HIF alphas, p300 and other transcription factors as well as trans-inhibitors like FIH. The endogenous promoter activity of VPF/VEGF will also be examined in RCCs in regard to PKC zeta and its regulators.
In Aim 2, we will investigate the mechanism of VPF/VEGF mRNA stability in RCCs. We will examine the involvement of PKC zeta and its associated molecules in the modulation of RNA-binding protein, HuR, that usually binds at 3'-translated regions of VPF/VEGF mRNA.
This aim will also elucidate the physical interactions between HuR and pVHL and its biological relevance. Finally, Aim 3 will extrapolate tissue culture data and reagents to animal models of RCC, seeking to understand the importance of VPF/VEGF as well as the mechanisms by which VPF/VEGF is activated in renal tumors; it is likely that we will propose new, specific targets for therapies that block angiogenesis and thereby tumor growth and metastasis. These experiments will provide new and important information on the mechanisms of carcinogenesis and suggest new targets for intervention in RCC, a common, highly vascular, angiogenesis-dependent carcinoma that is resistant to currently available therapies.
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