The p53-Associated Regulation of ATF4 mRNA Expression Involves p21 and p130 in a Stress-Dependent Manner

Abstract

Highlights What are the main findings? Chemotherapeutic agents targeting p53 downregulate ATF4 mRNA in a stress-dependent manner. p21 and p130 contribute to the specific p53-dependent downregulation of ATF4 mRNA upon mitochondrial dysfunction. ATF4 mRNA levels are reduced under hypoxic conditions and partially restored by p130 knockdown. What is the implication of the main findings? This study suggests the existence of a new link between p53 and ATF4. Abstract p53-dependent signaling and the integrated stress response (ISR) are major stress response programs that coordinate cellular metabolism and cell fate decisions. While p53 activation often promotes cell cycle arrest and cell death, the ISR can support either adaptive survival or cell death depending on the cellular context. Although increasing evidence indicates the crosstalk between these pathways, the underlying mechanisms remain incompletely understood. Here, we show that p53 activation is associated with reduced ATF4 mRNA expression under basal conditions and during selected metabolic stresses, including mitochondrial dysfunction. Knockdown experiments have demonstrated that p21 and p130 contribute to this response in a stress-dependent manner. Our findings identify a context-dependent link between p53 signaling and ATF4 mRNA regulation and suggest that p53, p21, and p130 may influence the ATF4-dependent branch of the ISR during cellular stress.