Margita Márton1, Nikolett Tihanyi2, Gábor Bánhegyi2, Orsolya Kapuy2
1 Semmelweis University, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Budapest
2 Semmelweis University, Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Budapest
Oxidative stress is considered as a redox imbalance between oxidative free radicals formation and antioxidant compounds of the cell. This imbalance can influence the cellular homeostasis by making damages and even leading to cell death. Treatment with oxidative agents (such as H2O2, TBHP) results in activation of the cellular stress response mechanism; meanwhile the ongoing cell division cycle has to be blocked. NRF2 (nuclear factor erythroid 2-related factor 2) has a key role in empowering cell adaptation to oxidative stress through transcriptionally controlling numerous cytoprotective genes. However, details about its effect on cell cycle regulation have not been explored yet. Cell cycle is a precisely regulated process driven by cyclin dependent kinase (CDK)/cyclin complexes that can be arrested by the molecules in the checkpoints in case of stress. Under oxidative stress, D-type cyclins seem to behave the most hypersensitive way.
Using molecular biological techniques, our goal is to reveal a crosstalk between the PERK substrate NRF2 and the cell cycle regulator Cyclin D1 during oxidative stress.
Treatments with oxidative stressor were combined with silencing PERK or NRF2 in HEK293T cells. Both protein’s silencing increased cell viability during oxidative stress. Cyclin D1 level was almost constant in siPERK and siNrf2 transfected and non-transfected cells too, but certain CDK inhibitors were down-regulated in silenced treatments.
We suggest that PERK kinase inhibits the cyclin molecule throughout NRF2 induction by various methods. We also assume that the indirect regulatory connection between NRF2 and Cyclin D1 is generated by CDK inhibitors (such as p15, p21 and p27).
This work was supported by the ÚNKP-17-3-I-SE-30 New National Excellence Program of the Ministry of Human Capacities.
Doctoral School: Molecular Medicine School of Ph.D. Studies
Supervisior: Gábor Bánhegyi, Orsolya Kapuy
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