PPM1D suppresses p53-dependent transactivation and cell death by inhibiting the Integrated Stress Response

• Published in: Nature communications 2022-12, Vol.13 (1), p.7400-16, Article 7400
• Main Authors: Andrysik, Zdenek, Sullivan, Kelly D., Kieft, Jeffrey S., Espinosa, Joaquin M.
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/2; 13/31; 13/44; 13/51; 13/89; 13/95; 14/19; 14/34; 38; 38/15; 38/77; 38/88; 38/91; 631/337/572; 631/67/1244; 64/60; 82/51; Animals; Apoptosis; Cancer; Cell Death; Cellular stress response; Clinical trials; Eukaryotic Initiation Factor-2 - genetics; Heme; Humanities and Social Sciences; Inhibition; Kinases; MDM2 protein; Mice; Mortality; multidisciplinary; Neoplasms; p53 Protein; Pharmacology; Phosphorylation; Protein Phosphatase 2C - metabolism; Repressors; Science; Science (multidisciplinary); Transcription Factors; Transcriptional Activation; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-35089-5

The p53 transcription factor is a master regulator of cellular stress responses inhibited by repressors such as MDM2 and the phosphatase PPM1D. Activation of p53 with pharmacological inhibitors of its repressors is being tested in clinical trials for cancer therapy, but efficacy has been limited by poor induction of tumor cell death. We demonstrate that dual inhibition of MDM2 and PPM1D induces apoptosis in multiple cancer cell types via amplification of the p53 transcriptional program through the eIF2α-ATF4 pathway. PPM1D inhibition induces phosphorylation of eIF2α, ATF4 accumulation, and ATF4-dependent enhancement of p53-dependent transactivation upon MDM2 inhibition. Dual inhibition of p53 repressors depletes heme and induces HRI-dependent eIF2α phosphorylation. Pharmacological induction of eIF2α phosphorylation synergizes with MDM2 inhibition to induce cell death and halt tumor growth in mice. These results demonstrate that PPM1D inhibits both the p53 network and the integrated stress response controlled by eIF2α-ATF4, with clear therapeutic implications. The authors describe a functional crosstalk between the p53 network and the integrated stress response through the p53 repressor PPM1D. Inhibition of PPM1D potentiates p53-dependent transactivation and apoptosis via induction of the HRI-eIF2α-ATF4 pathway.