A Role for RIP1 in Gliomagenesis

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DESCRIPTION (provided by applicant): Identification of molecular alterations and signaling abnormalities that initiate and maintain the malignant phenotype in glioblastoma (GBM) is a key step in designing treatment. The NF-?B and PI3K-Akt pathways are deregulated in GBM and likely to play key roles in the pathogenesis of GBM and in resistance to treatment. NF-?B activation is a hallmark of inflammation. In this proposal, we aim to characterize the role of the death domain containing kinase receptor interacting protein (RIP, RIP1), in the biology of GBM. RIP1 activates both the NF-?B and PI3K-Akt pathways in glioma cells. In addition, RIP1 negatively regulates two key tumor suppressor signaling networks, the PTEN and the p53 pathways. RIP1 levels are increased in up to 30% of GBMs but not in Grade II-III gliomas. Furthermore, RIP1 expression confers a worse prognosis in GBM, overexpressing RIP1 induces proliferation of glioma cells and silencing RIP1 inhibits proliferation of glioma cells in an animal model of glioma. The central hypothesis of this proposal is that RIP1 plays a key role in the pathogenesis of GBM and resistance to treatment by regulating key signaling pathways in tumor cells. The broad goal of this proposal is to demonstrate experimentally that RIP1 promotes the malignant phenotype of GBM. In Specific Aim 1, we will explore the mechanistic relationships coupling RIP1 to the proliferation of glioma cells and identify RIP1 specific effector mechanisms influencing proliferation and resistance to chemotherapy in glioma cells. In Specific Aim 2, we will determine the mechanisms and biological significance of RIP1 mediated inhibition of tumor suppressor signaling. In Specific Aim 3 we will benchmark the effect of RIP1 expression in glioma cells using an orthotropic animal model. This study may provide useful insights into the role of inflammation in GBM and help in the design of more effective treatments targeting inflammatory signaling pathways in GBM. PUBLIC HEALTH RELEVANCE: RIP1, a protein involved in inflammation, is highly expressed in GBM and confers a poor prognosis. We investigate the mechanisms used by RIP1 to promote growth of malignant glioma. Improved understanding of RIP1 in glioma may lead to design of more rational targeted treatment.