Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In add...Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirusmediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus（Reolysin） across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.展开更多
NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin ...NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin by binding and modulating the ubiquitin ligase substrate recognition factor β-TrCP. β-catenin is a major executor of the Wnt pathway. The ubiquitin SCF-β-TrCP ligase complex acts on a phospho-degron site in β-catenin that can be phosphorylated by GSK-3β. We now show that in addition to binding β-TrCP, NORE1A also promotes the phosphorylation of the β-catenin phospho-degron by complexing with the kinase GSK-3β. Indeed, NORE1A enhances the formation of a GSK-3β/β-TrCP complex. A structural mutant of NORE1A that retains β-TrCP binding but will no longer interact with GSK-3β inhibits the β-catenin degrading action of NORE1A. The GSK-3β interaction with NORE1A plays an important role in the biology of NORE1A as a GSK-3β inhibitor blocks NORE1A induced senescence. Thus, we identify a new role for the tumor suppressor NORE1A: The regulation of GSK-3β. GSK-3β has many other substrates including multiple transcription factors and co-activators such as p53 and the Hippo component TAZ. The work implies that NORE1A may be able to influence all of them via this new kinase scaffolding interaction.展开更多
文摘Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirusmediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus（Reolysin） across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.
文摘NORE1A (RASSF5) is a tumor suppressor of the RASSF family that is often down-regulated in human tumors. NORE1A has multiple roles in controlling cellular homeostasis, one of them being regulating levels of β-catenin by binding and modulating the ubiquitin ligase substrate recognition factor β-TrCP. β-catenin is a major executor of the Wnt pathway. The ubiquitin SCF-β-TrCP ligase complex acts on a phospho-degron site in β-catenin that can be phosphorylated by GSK-3β. We now show that in addition to binding β-TrCP, NORE1A also promotes the phosphorylation of the β-catenin phospho-degron by complexing with the kinase GSK-3β. Indeed, NORE1A enhances the formation of a GSK-3β/β-TrCP complex. A structural mutant of NORE1A that retains β-TrCP binding but will no longer interact with GSK-3β inhibits the β-catenin degrading action of NORE1A. The GSK-3β interaction with NORE1A plays an important role in the biology of NORE1A as a GSK-3β inhibitor blocks NORE1A induced senescence. Thus, we identify a new role for the tumor suppressor NORE1A: The regulation of GSK-3β. GSK-3β has many other substrates including multiple transcription factors and co-activators such as p53 and the Hippo component TAZ. The work implies that NORE1A may be able to influence all of them via this new kinase scaffolding interaction.
