Opposing functions of Ki- and Ha-Ras genes in the regulation of redox signals

• Published in: Current biology Vol. 11; no. 8; pp. 614 - 619
• Main Authors: Santillo, M, Mondola, P, Serù, R, Annella, T, Cassano, S, Ciullo, I, Tecce, M F, Iacomino, G, Damiano, S, Cuda, G, Paternò, R, Martignetti, V, Mele, E, Feliciello, A, Avvedimento, E V
• Format: Journal Article
• Language: English
• Published: England 17.04.2001
• Subjects: 3T3 Cells; Animals; Cell Line; Cercopithecus aethiops; COS Cells; ERK1 protein; ERK2 protein; Genes, ras - physiology; Ha-ras protein; Ki-ras protein; Mice; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; Oxidation-Reduction; p21 protein; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Rats; Reactive Oxygen Species - metabolism; Signal Transduction - physiology; Superoxide Dismutase - metabolism
• ISSN: 0960-9822
• DOI: 10.1016/S0960-9822(01)00159-2

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.