Abstract
Nuclear factor-kappaB (NF-kappaB) activation may play an important role in the pathogenesis of cancer and also in resistance to treatment. Inactivation of the p53 tumor suppressor is a key component of the multistep evolution of most cancers. Links between the NF-kappaB and p53 pathways are under intense investigation. In this study, we show that the receptor interacting protein 1 (RIP1), a central component of the NF-kappaB signaling network, negatively regulates p53 tumor suppressor signaling. Loss of RIP1 from cells results in augmented induction of p53 in response to DNA damage, whereas increased RIP1 level leads to a complete shutdown of DNA damage-induced p53 induction by enhancing levels of cellular mdm2. The key signal generated by RIP1 to up-regulate mdm2 and inhibit p53 is activation of NF-kappaB. The clinical implication of this finding is shown in glioblastoma, the most common primary malignant brain tumor in adults. We show that RIP1 is commonly overexpressed in glioblastoma, but not in grades II and III glioma, and increased expression of RIP1 confers a worse prognosis in glioblastoma. Importantly, RIP1 levels correlate strongly with mdm2 levels in glioblastoma. Our results show a key interaction between the NF-kappaB and p53 pathways that may have implications for the targeted treatment of glioblastoma.