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: During these experiments, we often observed an apparent increase in the levels of HIPK2 in the lysates of cells transfected with Ras and NORE1A (Fig. 4 d). This was particularly apparent when we examined the effects of activated Ras induction on endogenous HIPK2 levels (Fig. 4 e). HIPK2 is known to be an unstable protein (Calzado et al., 2009). By using cyclohexamide treatment to block translation after transient transfection of HEK-293 cells, we were able to analyze the effects of Ras and NORE1A on HIPK2 protein stability. We found that Ras acts to stabilize NORE1A and that both NORE1A and Ras stabilize HIPK2. The most effective stabilization was a combination of Ras and NORE1A. A representative experiment is shown in Fig. 5 a. Quantification of three experiments is shown below as relative percentage decay (Fig. 5 b).
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.