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

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.