Abstract
Oxidative stress results in activation of several signal transduction pathways controlled by the PERK-substrate NRF2 (nuclear factor erythroid 2-related factor 2); meanwhile the ongoing cell division cycle has to be blocked. It has been recently shown that Cyclin D1 got immediately down-regulated via PERK pathway in response to oxidative stress leading to cell cycle arrest. However, the effect of NRF2 on cell cycle regulation has not been explored yet. We aimed to reveal a crosstalk between PERK-substrate NRF2 and the key elements of cell cycle regulatory network upon oxidative stress using molecular biological techniques- Although Cyclin D1 level remained constant, its activity was blocked by various stoichiometric inhibitors (such as p15, p21 and p27) even at low level of oxidative stress. The activity of these CDK inhibitors completely disappeared, when the addition of oxidative agent was combined with silencing of either PERK or NRF2.This further confirms the important role of NRF2 in blocking Cyclin D1 with stoichiometric inhibitors at early stage of oxidative stress.
Highlights
From internal metabolism and external toxicant exposure several harmful reactive oxidants (such as reactive oxygen (ROS) and nitrogen (RNS) species) might be formed generating oxidative stress in the cell
In order to test the effect of nuclear factor erythroid 2-related factor 2 (NRF2) in cell cycle regulation first we set up a protocol to induce oxidative stress in human embryonic kidney cells (HEK293T) by using tert-butyl hydroperoxide (TBHP)
Oxidative stress generated by internal metabolism or environmental toxicant exposure affects many cellular functions, including various signalling pathways
Summary
From internal metabolism and external toxicant exposure several harmful reactive oxidants (such as reactive oxygen (ROS) and nitrogen (RNS) species) might be formed generating oxidative stress in the cell. A significant decrease in the antioxidant (e.g. glutathione) controlled cellular defence mechanism can lead to oxidative stress [1]. The highly reactive ROS and RNS molecules can be generated even at physiological conditions formed in a well-controlled manner, and they are used by the immune system as a way to remove pathogens [2]. Oxidative stress-generated effects are involved in neurodegenerative diseases (e.g. Parkinson’s disease), sickle-cell disease, toxicity of xenobiotics, heart failure and cancer development [3, 4]. Oxidative stress response mechanisms have to be highly controlled [2]
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