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 pas signaling messages. Chemicals with antioxidant activity suppress pas-induced DNA synthesis. The inhibition of pas 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.
Opposing functions of Ki- and Ha-Ras genes in the regulation of redox signals / Santillo, Mariarosaria; Mondola, Paolo; Seru', R; Annella, T; Cassano, S; Ciullo, I; Tecce, Mf; Iacomino, G; Damiano, S; Cuda, G; Paterno', Roberto; Martignetti, V; Mele, E; Feliciello, A; Avvedimento, VITTORIO ENRICO. - In: CURRENT BIOLOGY. - ISSN 0960-9822. - STAMPA. - 11:(2001), pp. 614-619. [10.1016/S0960-9822(01)00159-2]
Opposing functions of Ki- and Ha-Ras genes in the regulation of redox signals.
SANTILLO, MARIAROSARIA;MONDOLA, PAOLO;SERU' R;DAMIANO S;PATERNO', ROBERTO;AVVEDIMENTO, VITTORIO ENRICO
2001
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 pas signaling messages. Chemicals with antioxidant activity suppress pas-induced DNA synthesis. The inhibition of pas 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.