Cellular stress response pathways

Cellular stress response pathways represent a coordinated network of molecular signaling systems designed to maintain cellular homeostasis in the face of adverse environmental or physiological conditions (Fulda et al., 2010, Nature Reviews Drug Discovery). These pathways, including the Unfolded Protein Response (UPR), the Heat Shock Response (HSR), and the Integrated Stress Response (ISR), detect stressors such as proteotoxicity, oxidative damage, and nutrient deprivation (Walter & Ron, 2011, Science). Upon activation, they initiate adaptive programs that involve the upregulation of molecular chaperones, temporary inhibition of protein synthesis, and activation of DNA repair mechanisms. If the stress is persistent or irreparable, these pathways switch from pro-survival to pro-apoptotic signaling to eliminate the damaged cell (Tabas & Ron, 2011, Nature Cell Biology). In oncology, cancer cells often exploit these pathways to survive the hypoxic and nutrient-poor tumor microenvironment, making components like Hsp90 or the PERK-eIF2alpha axis attractive therapeutic targets (Luo et al., 2009, Cell). Conversely, in neurodegenerative diseases, enhancing these responses is explored as a strategy to clear misfolded protein aggregates (Hetz et al., 2013, Nature Reviews Drug Discovery).

Other names

Stress response networkIntegrated stress responseCellular homeostasis pathwaysProteotoxic stress responseISRUPRHSR

Modulation of protein folding via chaperone inhibition, regulation of translation initiation through eIF2alpha phosphorylation, and induction of proteasomal degradation or autophagy (Hetz et al., 2013, Nature Reviews Drug Discovery).