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Post-translational proteins modifications proteomic study - phosphorylation, s-nitrosylation and nitration - in triple negative breast cancer cell models

Grant number: 14/11295-4
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): August 01, 2014
Effective date (End): July 31, 2017
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
Principal researcher:Hugo Pequeno Monteiro
Grantee:Rita Tokikawa
Home Institution: Centro de Terapia Celular e Molecular. Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil


Reactions of NO* with O2, or with O2.-, leads to the formation of reactive nitrogen species (RNS) whose activity may be responsible for the effects attributed to NO*. RNS promote oxidative modifications in amino acids, or react with the iron-heme group in proteins/enzymes modulating cell signaling processes (Pacher et al, 2007). Oxidative-based post-translational modifications can positively or negatively modulate the phosphorylation levels of signaling proteins (Hess et al, 2005; Pacher et al, 2007; Monteiro et al, 2008.). Tyrosine nitration is a results of addition of the nitro group (NO2) usually at the 3-position of the phenolic ring of a tyrosine residue generating 3- nitrotyrosine (Beckman, 1996). At physiological pH, NO* reacts with O2.- forming peroxynitrite (ONOO-). The formation of ONOO- promotes oxidative damage to double-stranded DNA, protein and lipid oxidation. The protein nitration (3-nitrotyrosine) has been observed in cells and tissues. In addition to nitration of tyrosine, NO* can promote cysteine S-nitrosylation. S-nitrosylation involves the covalent incorporation of NO* moiety into the cysteine thiol side chain of proteins and peptides. S-nitrosylation plays an important role in cellular signal transduction pathways related to NO* reactivity. Unlike other post-translational modifications, S-nitrosylation is not dependent on the action of enzymes. The occurrence of S- nitrosylation depends on the reactivity of the nitrosating agent and on the redox microenvironment (Hess et al., 2005). In mammalian cells, NO* is synthesized by three isoforms of the enzyme nitric oxide synthase (NOS). In addition to O2, NOS require L-arginine as a substrate, cofactors and coenzymes such as nicotinamide adenine dinucleotide phosphate, tretrahydrobiopterin, flavin adenine dinucleotide, flavin mononucleotide and heme group. NO* induces cell death or tumor progression depending on its concentration. Cysteine S-nitrosylation and tyrosine nitration potentially regulate the activity of protein kinases and protein phosphatases affecting protein phosphorylation/dephosphorylation signaling pathways. By using proteomic analysis, we aimed to characterize the occurrence of post-translational modifications: S-nitrosylation, tyrosine nitration, and tyrosine phosphorylation, and how they interrelate in triple negative cancer cell model (MDA-MB 231 cells) stimulated to produce NO*. (AU)

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