title: Ras Regulates Rb via NORE1A.
abstract: Mutations in the Ras oncogene are one of the most frequent events in human cancer. Although Ras regulates numerous growth-promoting pathways to drive transformation, it can paradoxically promote an irreversible cell cycle arrest known as oncogene-induced senescence. Although senescence has clearly been implicated as a major defense mechanism against tumorigenesis, the mechanisms by which Ras can promote such a senescent phenotype remain poorly defined. We have shown recently that the Ras death effector NORE1A plays a critical role in promoting Ras-induced senescence and connects Ras to the regulation of the p53 tumor suppressor. We now show that NORE1A also connects Ras to the regulation of a second major prosenescent tumor suppressor, the retinoblastoma (Rb) protein. We show that Ras induces the formation of a complex between NORE1A and the phosphatase PP1A, promoting the activation of the Rb tumor suppressor by dephosphorylation. Furthermore, suppression of Rb reduces NORE1A senescence activity. These results, together with our previous findings, suggest that NORE1A acts as a critical tumor suppressor node, linking Ras to both the p53 and the Rb pathways to drive senescence.
authors.affiliation: From the Departments of Biochemistry and Molecular Genetics.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Barnoud
authors.affiliation: Medicine, and.
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.affiliation: Pharmacology and Toxicology, James Graham Brown Cancer Center, Molecular Targets Program, University of Louisville, Louisville, Kentucky 40202 gjclar01@louisville.edu.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Clark
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D019556:COS Cells; D016922:Cellular Senescence / Q000235:genetics; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C117307:KRAS protein, human; C454042:RASSF5 protein, human; D016160:Retinoblastoma Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D054645:Protein Phosphatase 1; C501009:HRAS protein, human; D020559:Monomeric GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras)
keywords: NORE1A; RASSF; Ras protein; cancer; cellular senescence; protein phosphorylation; retinoblastoma protein (pRb, RB)