Project: Research project

Project Details


DESCRIPTION: (adapted from the investigator's abstract) In order to grow
beyond minimal size, tumors must induce a new blood supply. Like many human
carcinomas, renal cell carcinomas (RCC) are thought to induce angiogenesis
by secreting an angiogenic cytokine, vascular permeability factor, also
known as vascular endothelial growth factor (VPF/VEGF). Studies from
several laboratories, including our own, have shown that a number suppressor
gene, the von Hippel Lindau (VHL) gene, has an important role in regulating
VPF/VEGF expression in RCC and that this regulation involves both
transcriptional and post-transcriptional events. More recently, they have
found that wild-type VHL (wt-VHL) selectively interactions with and thereby
down-regulates the activities of two protein kinase C (PKC) isoforms, rho
and sigma; when VHL is as functional, as in RCC, VPF/VEGF is overexpressed,
suggesting that PKC rho and sigma are on the signaling pathway(s) by which
VHL regulates VPF/VEGF expression. Other evidence suggests that oncogenes,
notable Ras and Src, also regulate VPF/VEGF expression in several important
tumors, likely also including RCC. The experiments proposed here are
designed to investigate more carefully the signaling pathways by which a
tumor suppressor gene (VHL) and oncogenes (Ras, Src) induce VPF/VEGF
overexpression and thus angiogenesis in RCC. A first Aim will make use of
dominant negative mutants of PKC rho and sigma in RCC cells to investigate
the role of PKC rho and sigma in regulating VPF/VEGF expression at both
transcriptional and post-transcriptional levels. The nature and
consequences of physical interaction between PKC and wt-VHL will also be
explored. For Aim 2, dominant negative mutants of Ras and Src will be
utilized to investigate whether and by what pathways these signaling
components regulate VPF/VEGF expression in RCC. Finally, a third Aim will
determine whether RCC cells transfected with dominant negative mutants of
PKC rho and sigma or of other protein kinases along the signaling pathways
which regulate VPF/VEGF expression, down-regulate VPF/VEGF and inhibit tumor
angiogenesis and growth in an animal model. 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
StatusNot started


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