1. HGF/c-Met regulates p22phox subunit of the NADPH oxidase complex in primary mouse hepatocytes by transcriptional and post-translational mechanisms
- Author
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Leticia Bucio, Denise Clavijo-Cornejo, Soraya Salas-Silva, Roxana U. Miranda-Labra, Luis Enrique Gómez-Quiroz, Alejandro Escobedo-Calvario, Verónica Souza, María Concepción Gutiérrez-Ruiz, and Arturo Simoni-Nieves
- Subjects
C-Met ,medicine.medical_treatment ,Specialties of internal medicine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,NADPH oxidase complex ,Gene expression ,medicine ,HGF ,c-Met ,NADPH oxidase ,Hepatology ,biology ,business.industry ,Growth factor ,General Medicine ,Cell biology ,RC581-951 ,chemistry ,030220 oncology & carcinogenesis ,Hepatocytes ,biology.protein ,030211 gastroenterology & hepatology ,Hepatocyte growth factor ,P22phox ,p22phox ,Signal transduction ,business ,medicine.drug - Abstract
Introduction and objectives It is well-known that signaling mediated by the hepatocyte growth factor (HGF) and its receptor c-Met in the liver is involved in the control of cellular redox status and oxidative stress, particularly through its ability to induce hepatoprotective gene expression by activating survival pathways in hepatocytes. It has been reported that HGF can regulate the expression of some members of the NADPH oxidase family in liver cells, particularly the catalytic subunits and p22phox. In the present work we were focused to characterize the mechanism of regulation of p22phox by HGF and its receptor c-Met in primary mouse hepatocytes as a key determinant for cellular redox regulation. Materials and methods Primary mouse hepatocytes were treated with HGF (50 ng/mL) at different times. cyba expression (gene encoding p22phox) or protein content were addressed by real time RT-PCR, Western blot or immunofluorescence. Protein interactions were explored by immunoprecipitation and FRET analysis. Results Our results provided mechanistic information supporting the transcriptional repression of cyba induced by HGF in a mechanism dependent of NF-κB activity. We identified a post-translational regulation mechanism directed by p22phox degradation by proteasome 26S, and a second mechanism mediated by p22phox sequestration by c-Met in plasma membrane. Conclusion Our data clearly show that HGF/c-Met exerts regulation of the NADPH oxidase by a wide-range of molecular mechanisms. NADPH oxidase-derived reactive oxygen species regulated by HGF/c-Met represents one of the main mechanisms of signal transduction elicited by this growth factor.
- Published
- 2021