title: Opposing functions of Ki- and Ha-Ras genes in the regulation of redox signals.
abstract: Ras p21 signaling is involved in multiple aspects of growth, differentiation, and stress response [1-2]. There is evidence pointing to superoxides as relays of Ras signaling messages. Chemicals with antioxidant activity suppress Ras-induced DNA synthesis. The inhibition of Ras significantly reduces the production of superoxides by the NADPH-oxidase complex [3]. Kirsten and Harvey are nonallelic Ras cellular genes that share a high degree of structural and functional homology. The sequences of Ki- and Ha-Ras proteins are almost identical. They diverge only in the 20-amino acid hypervariable domain at the COOH termini. To date, their functions remain indistinguishable [4]. We show that Ki- and Ha-Ras genes differently regulate the redox state of the cell. Ha-Ras-expressing cells produce high levels of reactive oxygen species (ROS) by inducing the NADPH-oxidase system. Ki-Ras, on the other hand, stimulates the scavenging of ROS by activating posttranscriptionally the mitochondrial antioxidant enzyme, Mn-superoxide dismutase (Mn-SOD), via an ERK1/2-dependent pathway. Glutamic acid substitution of the four lysine residues in the polybasic stretch at the COOH terminus of Ki-Ras completely abolishes the activation of Mn-SOD, although it does not inhibit ERK1/2-induced transcription. In contrast, an alanine substitution of the cysteine of the CAAX box has very little effect on Mn-SOD activity but eliminates ERK1/2- dependent transcription.
authors.affiliation: Dipartimento di Neuroscienze e di Scienze del Comportamento-Sezione di Fisiologia, Napoli, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Santillo
authors.forename: P
authors.initials: P
authors.lastname: Mondola
authors.forename: R
authors.initials: R
authors.lastname: Serù
authors.forename: T
authors.initials: T
authors.lastname: Annella
authors.forename: S
authors.initials: S
authors.lastname: Cassano
authors.forename: I
authors.initials: I
authors.lastname: Ciullo
authors.forename: M F
authors.initials: MF
authors.lastname: Tecce
authors.forename: G
authors.initials: G
authors.lastname: Iacomino
authors.forename: S
authors.initials: S
authors.lastname: Damiano
authors.forename: G
authors.initials: G
authors.lastname: Cuda
authors.forename: R
authors.initials: R
authors.lastname: Paternò
authors.forename: V
authors.initials: V
authors.lastname: Martignetti
authors.forename: E
authors.initials: E
authors.lastname: Mele
authors.forename: A
authors.initials: A
authors.lastname: Feliciello
authors.forename: E V
authors.initials: EV
authors.lastname: Avvedimento
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D011905:Genes, ras / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase