Disulfide relays and phosphorylative cascades: partners in redox-mediated signaling pathways

Abstract

Modifications of specific amino-acid residues of proteins are fundamental in order to modulate different signaling processes among which the cascade of phosphorylation represents the most effective example. Recently, also, the modification of the redox state of cysteine residues of certain proteins, which is a widespread mechanism in the regulation of protein function, has been proposed to be involved in signaling pathways. Growing evidence shows that some transcription factors could be modulated by both oxidation and phosphorylation. In particular, the pathways regulated by the mitogen activated protein (MAP) kinases represent well-established examples of the cross talk between redoxmediated signaling and phosphorylative cascades. This review will compare the two modes of signal transduction and propose an evolutionary model of a partnership of the two mechanisms in the eukaryotic cell, with redox-mediated signals being more specific and ancestral and phosphorylative signals being more diffuse but predominant in signal propagation.

trans-Resveratrol induces apoptosis in human breast cancer cells MCF-7 by the activation of MAP kinases pathways

“…The direct relationship between alteration of intracellular redox state and activation of MAP kinases-mediated phosphorylative pathways has been exhaustively demonstrated [15]. Moreover, a role for polyphenols in the activation of different MAP kinases members has been suggested as necessary event for downstream induction of apoptosis in cancer cells [31].…”

“…MAP kinases are serine/threonine kinases that are regulated by a variety of extracellular stimuli including growth factors, mitogens, cytokines and environmental stresses [39]. Oxidative stress-mediated apoptosis is induced by phosphorylative cascades; indeed, in the last few years a hypothesis has emerged that reactive oxygen species (ROS) are not only the downstream damaging species produced by radical chain reactions, but also the second messengers of signaling networks [15].…”

Oxidative Therapy Against Cancer

“…It is known that ROS may serve as cellular messengers in the signal translation pathway and also an increase of ROS may trigger cell growth and proliferation, contributing to cancer development (Filomeno et al, 2005). Uncontrolled tumor cell proliferation requires the up-regulation of multiple intracellular signaling pathways, including cascades involved in survival, proliferation, and cell cycle progression.…”

Disulfide Bond-mediated Multimerization of Ask1 and Its Reduction by Thioredoxin-1 Regulate H2O2-induced c-Jun NH2-terminal Kinase Activation and Apoptosis

“…Modification of cysteine is a posttranslational modification emerging as a new mechanism for the regulation of protein (Filomeni et al, 2005). In bacteria and yeast, oxidation leading to the formation of intramolecular disulfide bonds and activation of the transcriptional factors OxyR and Yap1 play an important role in the response of these organisms to oxidative stress (Zheng et al, 1998;Delaunay et al, 2002).…”

“…H 2 O 2 can oxidize cysteine residues to the sulfenic (protein-SOH), sulfinic (protein-SO 2 H), and sulfonic acid (protein-SO 3 H) forms, also leading to intra-or intermolecular disulfide bonds (protein-SS-protein) and to protein glutathionylation (protein-SSG). Similarly to protein posttranslational modification by serine, threonine, and tyrosine phosphorylation, oxidation of cysteine residues can trigger changes in protein conformation and activity (Filomeni et al, 2005). In bacteria, OxyR is an archetypical H 2 O 2 sensor at the top of a redox-sensitive pathway, being activated by H 2 O 2 through formation of an intramolecular disulfide bond and controlling the transcription of antioxidant defense genes (Storz and Tartaglia, 1992;Zheng et al, 1998).…”