The Receptor Interacting Protein 1 Inhibits p53 Induction through NF-¿B Activation and Confers a Worse Prognosis in Glioblastoma
Seongmi Park Cancer Research,
NF-¿B 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 multi-step evolution of most cancers. Links between the NF-¿B and p53 pathways are under intense investigation. In this study, we show that the receptor interacting protein (RIP, RIP1), a central component of the NF-¿B signaling network, negatively regulates p53 tumor suppressor signaling. Loss of RIP1 from cells results in augmented induction of p53 in response to DNA damage, while 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 upregulate mdm2 and inhibit p53 is activation of NF-¿B. The clinical implication of this finding is demonstrated in glioblastoma (GBM), the most common primary malignant brain tumor in adults. We show that RIP1 is commonly overexpressed in GBM but not in grade II-III glioma and increased expression of RIP1 confers a worse prognosis in GBM. Importantly, RIP1 levels correlate strongly with mdm2 levels in GBM. Our results demonstrate a key interaction between the NF-¿B and p53 pathways that may have implications for the targeted treatment of GBM.