12/15-lipoxygenase contributes to platelet-derived growth factor-induced activation of signal transducer and activator of transcription 3.
J Biol Chem
; 288(49): 35592-603, 2013 Dec 06.
Article
em En
| MEDLINE
| ID: mdl-24165129
ABSTRACT
We showed previously that the small molecule indirubin-3'-monoxime (I3MO) prevents vascular smooth muscle cell (VSMC) proliferation by selectively inhibiting signal transducer and activator of transcription 3 (STAT3). Looking for the underlying upstream molecular mechanism, we here reveal the important role of reactive oxygen species (ROS) for PDGF-induced STAT3 activation in VSMC. We show that neither NADPH-dependent oxidases (Noxes) nor mitochondria, but rather 12/15-lipoxygenase (12/15-LO) are pivotal ROS sources involved in the redox-regulated signal transduction from PDGFR to STAT3. Accordingly, pharmacological and genetic interference with 12/15-LO activity selectively inhibited PDGF-induced Src activation and STAT3 phosphorylation. I3MO is able to blunt PDGF-induced ROS and 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) production, indicating an inhibitory action of I3MO on 12/15-LO and consequently on STAT3. We identify 12/15-LO as a hitherto unrecognized signaling hub in PDGF-triggered STAT3 activation and show for the first time a negative impact of I3MO on 12/15-LO.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Araquidonato 12-Lipoxigenase
/
Araquidonato 15-Lipoxigenase
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Proteínas Proto-Oncogênicas c-sis
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Fator de Transcrição STAT3
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article