The Important Role of Protein Kinases in the p53 Sestrin Signaling Pathway

Abstract

p53, a crucial tumor suppressor and transcription factor, plays a central role in the maintenance of genomic stability and the orchestration of cellular responses such as apoptosis, cell cycle arrest, and DNA repair in the face of various stresses. Sestrins, a group of evolutionarily conserved proteins, serve as pivotal mediators connecting p53 to kinase-regulated anti-stress responses, with Sestrin 2 being the most extensively studied member of this protein family. These responses involve the downregulation of cell proliferation, adaptation to shifts in nutrient availability, enhancement of antioxidant defenses, promotion of autophagy/mitophagy, and the clearing of misfolded proteins. Inhibition of the mTORC1 complex by Sestrins reduces cellular proliferation, while Sestrin-dependent activation of AMP-activated kinase (AMPK) and mTORC2 supports metabolic adaptation. Furthermore, Sestrin-induced AMPK and Unc-51-like protein kinase 1 (ULK1) activation regulates autophagy/mitophagy, facilitating the removal of damaged organelles. Moreover, AMPK and ULK1 are involved in adaptation to changing metabolic conditions. ULK1 stabilizes nuclear factor erythroid 2-related factor 2 (Nrf2), thereby activating antioxidative defenses. An understanding of the intricate network involving p53, Sestrins, and kinases holds significant potential for targeted therapeutic interventions, particularly in pathologies like cancer, where the regulatory pathways governed by p53 are often disrupted.

Unraveling the Role of Reactive Oxygen Species in T Lymphocyte Signaling

“…Upon the induction of oxidative stress, Keap1 releases Nrf2, allowing Nrf2 to stabilize and translocate into the nucleus. Once in the nucleus, Nrf2 initiates an antioxidative response, protecting cells from oxidative stress and the accumulation of cellular damage [ 90 , 111 , 112 , 113 , 114 ]. In particular, Nrf2 is involved in modulating the anti-inflammatory response by controlling redox balance and activating Antioxidant Response Enzyme (ARE)-mediated anti-inflammatory genes.…”

“…Damage to proteins and lipids not only disrupts intracellular signaling but also leads to cell death. DNA oxidation results in the accumulation of mutations, which can cause the development of malignancies [ 111 , 115 ]. If regulation of the redox balance is disrupted due to alterations in the Nrf2/Keap1 signaling pathway, it can lead to increased oxidative damage and mutations, thereby raising the risk of tumor development [ 115 , 116 , 117 , 118 ].…”