Nitrosative/Oxidative Stress Conditions Regulate Thioredoxin-Interacting Protein (TXNIP) Expression and Thioredoxin-1 (TRX-1) Nuclear Localization

Autor(es)

Ogata, Fernando Toshio ^{[1, 2]} ; Batista, Wagner Luiz ^[3] ; Sartori, Adriano ^{[1, 2]} ; Gesteira, Tarsis Ferreira ^{[1, 2]} ; Masutani, Hiroshi ^[4] ; Arai, Roberto Jun ^[5] ; Yodoi, Junji ^[4] ; Stern, Arnold ^[5] ; Monteiro, Hugo Pequeno ^{[1, 2]}

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Paulo, Dept Bioquim Biol Mol, Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, CTCMol, Ctr Cellular & Mol Therapy, Sao Paulo - Brazil

^[3] Univ Fed Sao Paulo, Dept Ciencias Biol, Sao Paulo - Brazil

^[4] Kyoto Univ, Dept Biol Responses, Kyoto - Japan

^[5] NYU, Sch Med, Dept Pharmacol, New York, NY - USA

• Tipo de documento: Artigo Científico
• Fonte: PLoS One; v. 8, n. 12 DEC 20 2013.
• Citações Web of Science: 17

Resumo

Thioredoxin (TRX-1) is a multifunctional protein that controls the redox status of other proteins. TRX-1 can be found in the extracellular milieu, cytoplasm and nucleus, and it has distinct functions in each environment. Previously, we studied the intracellular localization of TRX-1 and its relationship with the activation of the p21Ras - ERK1/2 MAP Kinases signaling pathway. In situations where this pathway was activated by stress conditions evoked by a nitrosothiol, S-nitroso-N-acetylpenicillamine (SNAP), TRX-1 accumulated in the nuclear compartment due to nitrosylation of p21Ras and activation of downstream ERK1/2 MAP kinases. Presently, we demonstrate that ERK1/2 MAP Kinases activation and spatial distribution within cells trigger TRX-1 nuclear translocation through downregulation of the physiological inhibitor of TRX-1, Thioredoxin Interacting Protein (TXN1P). Once activated by the oxidants, SNAP and H2O2, the ERK1/2 MAP kinases migrate to the nucleus. This is correlated with down-regulation of TXN1P. In the presence of the MEK inhibitors (PD98059 or U0126), or in cells transfected with the Protein Enriched in Astrocytes (PEA-15), a cytoplasmic anchor of ERK1/2 MAP kinases, TRX-1 nuclear migration and TXNIP down-regulation are no longer observed in cells exposed to oxidants. On the other hand, over-expression of TXNIP abolishes nuclear migration of TRX-1 under nitrosative/oxidative stress conditions, whereas gene silencing of TXNIP facilitates nuclear migration even in the absence of stress conditions. Studies based on the TXNIP promoter support this regulation. In conclusion, changes in TRX-1 compartmentalization under nitrosative/oxidative stress conditions are dependent on the expression levels of TXNIP, which are regulated by cellular compartmentalization and activation of the ERK1/2 MAP kinases. (AU)

• Processo FAPESP: 09/50708-4 - Regulacao da expressao genica de txnip, inibidora fisiologica da tiorredoxina, sob estimulo de especies reativas do oxigenio e do nitrogenio: dependencia da ativacao de map quinases
• Beneficiário: Fernando Toshio Ogata
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 07/59617-6 - Estudos da compartimentalização celular da proteína G de baixo peso molecular Ras e da proteína antioxidante tiorredoxina sob estímulo de fontes geradoras de óxido nítrico
• Beneficiário: Hugo Pequeno Monteiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 06/53791-1 - Estudo da associacao da tiorredoxina com as erk1/2 map quinases durante a migracao nuclear da tiorredoxina induzida por oxido nitrico.
• Beneficiário: Fernando Toshio Ogata
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 12/10470-1 - O papel do óxido nítrico e da enzima óxido nítrico sintase induzível na progressão de tumores humanos de cólon
• Beneficiário: Hugo Pequeno Monteiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/52730-7 - Estudo do papel do oxido nitrico na ativacao da gtpase rac-1 e seu envolvimento na manutencao e progressao da metastase tumoral em modelo de melanoma murino.
• Beneficiário: Hugo Pequeno Monteiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular