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: NORE1A can modulate apoptosis by binding to the MST kinases that regulate the Hippo pathway using its C-terminal SARAH motif (Khokhlatchev et al., 2002). Yet it can modulate cell cycle arrest in an MST kinase-independent manner (Aoyama et al., 2004). To determine if the senescence-activating effects of NORE1A were dependent on the Hippo signaling pathway, we generated a deletion mutant of NORE1A (NORE1A-delSARAH) that lacks the region containing the SARAH motif essential for its interaction with MST kinases (Khokhlatchev et al., 2002). We then repeated the senescence assays in A549 cells including the mutant NORE1A. The deletion mutant retained almost WT levels of senescence induction in A549 cells (Fig. 3).
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.