NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2.
Bottom Line: We show that NORE1A is a powerful Ras senescence effector and that down-regulation of NORE1A suppresses senescence induction by Ras and enhances Ras transformation.NORE1A acts to suppress its proapoptotic phosphorylation of p53 but enhance its prosenescent acetylation of p53.Thus, we identify a major new Ras signaling pathway that links Ras to the control of specific protein acetylation and show how NORE1A allows Ras to qualitatively modify p53 function to promote senescence.
Affiliation: Department of Medicine, Department of Biochemistry and Molecular Biology, Department of Pharmacology and Toxicology, J.G. Brown Cancer Center, Molecular Targets Group, University of Louisville, Louisville, KY 40202.Show MeSH
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Mentions: The aforementioned experiments implicate NORE1A as a key Ras senescence effector that acts via p53 but does not use the canonical Hippo pathway. While attempting to determine the mechanism behind the effect, we examined the subcellular localization of endogenous NORE1A and found that it is primarily localized to the nucleus (Fig. 4 a). Transient transfections of NORE1A tagged with GFP confirmed a mainly nuclear localization but also revealed that some cells demonstrated NORE1A in nuclear speckles (Fig. 4 b, top). Systematic analysis of a series of fluorescently tagged known nuclear speckle proteins showed that NORE1A specifically co-localized with the kinase HIPK2, a known regulator of p53 (Puca et al., 2010; Fig. 4 b, bottom). Further analysis confirmed that endogenous NORE1A could be co-immunoprecipitated with endogenous HIPK2 from HuH6 and HepG2 liver cancer cell lines (Fig. 4 c).
Affiliation: Department of Medicine, Department of Biochemistry and Molecular Biology, Department of Pharmacology and Toxicology, J.G. Brown Cancer Center, Molecular Targets Group, University of Louisville, Louisville, KY 40202.