NYMC Faculty Publications
Biochemical and Cellular Evidence Demonstrating AKT-1 as A Binding Partner for Resveratrol Targeting aProtein NQO2
Author Type(s)
Faculty
DOI
10.1371/journal.pone.0101070
Journal Title
PLoS One
First Page
101070
Last Page
101070
Document Type
Article
Publication Date
1-1-2014
Department
Biochemistry and Molecular Biology
Keywords
Carrier Proteins, Cell Line, Enzyme Activation, Gene Expression, Gene Knockdown Techniques, Humans, Hydrogen Bonding, Models, Molecular, Protein Binding, Protein Conformation, Protein Stability, Protein Transport, Proto-Oncogene Proteins c-akt, Quinone Reductases, RNA Stability, Resveratrol, Stilbenes
Disciplines
Medicine and Health Sciences
Abstract
BACKGROUND: AKT plays an important role in the control of cell proliferation and survival. Aberrant activation of AKT frequently occurs in human cancers making it an attractive drug targets and leading to the synthesis of numerous AKT inhibitors as therapeutic candidates. Less is known regarding proteins that control AKT. We recently reported that quinone reductase 2 (NQO2) inhibited AKT activity, by unknown mechanisms.
METHODOLOGY/PRINCIPAL FINDINGS: In this study, molecular modeling was used to query interaction between NQO2 and AKT. We found that pleckstrin homology (PH) and kinase domains of AKT bind to chains A and B of NQO2. Pull-down and deletion assays revealed that PH domain of AKT is essential for interaction with NQO2. Modeling analysis further revealed that kinase domain of AKT binds NQO2 in the vicinity of asparagine 161 located in the resveratrol-binding domain of NQO2. In studies to test whether exposure to resveratrol potentiates or diminishes AKT binding to NQO2, we showed that pre-binding by resveratrol in wild type but not histidine-161 (N161H) mutant NQO2 significantly affected this interaction. To obtain information on interplay between resveratrol and AKT, resveratrol affinity chromatography was performed. AKT binds with high affinity to the column suggesting that it is a target of resveratrol. The half-life of AKT mRNA decreased from ∼4 h in control cells to ∼1 h in NQO2-knockdown cells. The inhibition of AKT by resveratrol was attenuated in NQO2-expressing relative to NQO2-knockdown cells.
CONCLUSION/SIGNIFICANCE: Both NQO2 and AKT are targets of resveratrol; NQO2:AKT interaction is a novel physiological regulator of AKT activation/function.
Recommended Citation
Hsieh, T., Lin, C., Bennett, D. J., Wu, E., & Wu, J. M. (2014). Biochemical and Cellular Evidence Demonstrating AKT-1 as A Binding Partner for Resveratrol Targeting aProtein NQO2. PLoS One, 9 (6), 101070-101070. https://doi.org/10.1371/journal.pone.0101070
