p21 and p130 Mediate p53-Dependent Repression of ATF4 Transcription

p53-dependent signaling and the integrated stress response are the major programs aimed at fine-tuning cell metabolism and determining cell fate in the presence of stress stimuli. While activation of p53 more often results in proliferation inhibition and cell death than pro-survival adaptation, ISR can lead to distinct outcomes depending on cell context, either promoting cell survival or inducing cell death. Recent data indicate the existence of a cross-talk between these networks; however, the underlying mechanisms are still to be elucidated. Here, we have demonstrated that p53 can transcriptionally repress ATF4, one of the key players of ISR, either in the absence or presence of various metabolic stresses, such as mitochondrial dysfunction. We have shown that this effect partially relies on the p53 target p21^Cip1/Waf1 and the Rb family protein p130, which mediate p53-dependent transcriptional repression of target genes. Our findings shed light on a new possible mechanism behind the interplay of p53 and the ATF4-dependent branch of ISR, which is likely to play an essential role in cell metabolic adaptation and cell fate decisions.