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.

Keywords: Sestrins; autophagy; mTORC; mitophagy; nuclear factor erythroid 2-related factor 2 (Nrf2); p53; stress response.

Figure 1

p53 is a tumor suppressor protein activated by cellular stressors, including DNA damage, ER stress, oxidative stress, and metabolic stress. The Sestrin (SESN) family comprises Sestrin 1, 2, and 3, which are target genes of p53. The graphic was created using BioRender (www.biorender.com).

Figure 2

Activated p53 stimulates the expression of Sestrins. Sestrins, in turn, induce anti-stress responses, including the deceleration of cell proliferation and adaptation to changing nutrient conditions through mTORC1 inhibition, the promotion of autophagy/mitophagy for organelle quality control, and the initiation of an unfolded protein response (UPR) to prevent the accumulation of misfolded proteins. The graphic was created using BioRender (www.biorender.com).

Figure 3

Sestrins activate AMPK, and AMPK phosphorylates and activates TSC, which, in turn, inhibits mTORC1. Additionally, Sestrins can also inhibit GATOR2, resulting in the inhibition of mTORC1 through GATOR1. The inhibition of mTORC1 and activation of AMPK can further increase the activity of mTORC2. The inhibition of mTORC1 slows down cell proliferation, while the activation of mTORC2 allows the cell to adapt to changing nutrient conditions. The graphic was created using BioRender (www.biorender.com).

Figure 4

(Left panel): Oxidative stress can induce p53 activation, which in turn triggers the activation of Sestrins. Sestrins subsequently promote the degradation of Keap1 via ULK, resulting in the accumulation and activation of Nrf2 and the induction of an antioxidative stress response. (Right panel): In the absence of oxidative stress, Nrf2 is bound to Keap1, which triggers the degradation of Nrf2. The graphic was created using BioRender (www.biorender.com).

Figure 5

Sestrins inhibit mTORC1, thereby enabling the activation of the kinase ULK1. This activation leads to the assembly of a complex consisting of phosphorylated ULK1, FIP200, Atg13, and Atg101, initiating the process of autophagy. ULK1 can also phosphorylate Beclin1, which forms a complex with Parkin. This complex relocates to the mitochondria, where, in conjunction with PINK1, it triggers mitophagy, a specific form of autophagy. Mitophagy is responsible for eliminating damaged mitochondria, thereby preventing malfunctions and excessive ROS production. The graphic was created using BioRender (www.biorender.com).