title: NORE1A is a Ras senescence effector that controls the apoptotic/senescent balance of p53 via HIPK2.
abstract: The Ras oncoprotein is a key driver of cancer. However, Ras also provokes senescence, which serves as a major barrier to Ras-driven transformation. Ras senescence pathways remain poorly characterized. NORE1A is a novel Ras effector that serves as a tumor suppressor. It is frequently inactivated in tumors. 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. We show that Ras induces the formation of a complex between NORE1A and the kinase HIPK2, enhancing HIPK2 association with p53. HIPK2 is a tumor suppressor that can induce either proapoptotic or prosenescent posttranslational modifications of p53. 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.
authors.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.
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.affiliation: University of Griefswald, 17489 Greifswald, Germany.
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.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.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Barnoud
authors.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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clark
authors.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.
authors.forename: M Lee
authors.initials: ML
authors.lastname: Schmidt
authors.affiliation: Research Analysis and Evaluation Branch, National Cancer Institute, Rockville, MD 20850.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Vos
authors.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 gjclar01@louisville.edu.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Clark
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D063646:Carcinogenesis / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D016922:Cellular Senescence; D002522:Chlorocebus aethiops; D004795:Enzyme Stability; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C454042:RASSF5 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases; C501009:HRAS protein, human; D020559:Monomeric GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras)