p53 induces ARTS to promote mitochondrial apoptosis

• DOI: 10.1038/s41419-021-03463-8
• Publication Date: 2021-02-24T15:16:12Z
• Authors: Qian Hao; Jiaxiang Chen; Junming Liao; Yingdan Huang; Yu Gan; Sarit Larisch; Shelya X. Zeng; Hua Lu; Xiang Zhou
• Keywords: Transcriptional Activation; Indoles; bcl-X Protein; Antineoplastic Agents; Apoptosis; Article; 03 medical and health sciences; Phenothiazines; Neoplasms; Animals; Humans; Promoter Regions, Genetic; Mice, Knockout; 0303 health sciences; Binding Sites; QH573-671; HCT116 Cells; Mitochondria; Up-Regulation; Gene Expression Regulation, Neoplastic; Tumor Suppressor Protein p53; Cytology; Septins; Protein Binding; Signal Transduction

AbstractApoptosis related protein in TGF-β signaling pathway (ARTS) was originally discovered in cells undergoing apoptosis in response to TGF-β, but ARTS also acts downstream of many other apoptotic stimuli. ARTS induces apoptosis by antagonizing the anti-apoptotic proteins XIAP and Bcl-2. Here we identified the pro-apoptotic Sept4/ARTS gene as a p53-responsive target gene. Ectopic p53 and a variety of p53-inducing agents increased both mRNA and protein levels of ARTS, whereas ablation of p53 reduced ARTS expression in response to multiple stress conditions. Also, γ-irradiation induced p53-dependent ARTS expression in mice. Consistently, p53 binds to the responsive DNA element on the ARTS promoter and transcriptionally activated the promoter-driven expression of a luciferase reporter gene. Interestingly, ARTS binds to and sequesters p53 at mitochondria, enhancing the interaction of the latter with Bcl-XL. Ectopic ARTS markedly augments DNA damage stress- or Nutlin-3-triggered apoptosis, while ablation of ARTS preferentially impairs p53-induced apoptosis. Altogether, these findings demonstrate that ARTS collaborates with p53 in mitochondria-engaged apoptosis.