Simple Summary Cells experience various stress conditions, including replicative stress, oxidative stress, toxin-induced damage, and pathogen exposure. The tumor suppressor p53 initiates intricate cellular responses to mitigate such stress. Sestrins, induced by p53, play a pivotal role in these responses. The Sestrin family has three members, with Sestrin 2 being the most extensively studied. Here, all three Sestrins are considered, with a special focus on Sestrin 2. Sestrins trigger complex signaling cascades involving kinases and kinase complexes such as mTORC, AMP-activated kinase (AMPK), and Unc-51-like protein kinase 1 (ULK1). These kinase-driven responses enable cells to defend against cellular stress, facilitate repairs, and adapt to changing conditions, preventing damage accumulation in macromolecules such as nucleic acids, proteins, and lipids, and thereby averting malignant transformation. Thus, Sestrins essentially contribute to the prevention of cancer development. Because Sestrins also support adaptation to cellular stress and can thereby promote cell survival, these stress responses can also protect malignant tumor cells. Therefore, such anti-stress responses are a double-edged sword-on the one hand they prevent the onset of neoplasia, but on the other hand they can also shield an already established malignancy from the induction of cell death.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.
