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The ARTS of p53-dependent mitochondrial apoptosis
Qian Hao1,2,† , Jiaxiang Chen3,4,† , Hua Lu5 , Xiang Zhou1,2,6,7,*
1Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
3Department of Physiology, Medical College of Nanchang University, Nanchang 330006, China
4Jiangxi Provincial Key Laboratory of Reproductive Physiology and Pathology, Nanchang University, Nanchang 330006, China
5Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
6Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China
7Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
These authors contributed equally to this work
*Correspondence to:Xiang Zhou ,
J Mol Cell Biol, Volume 14, Issue 10, October 2022, mjac074,
Keyword: p53, ARTS, SEPT4, BCL-2 family, apoptosis, cancer therapy

The tumor-suppressive activity of p53 is largely attributed to its ability to induce cell death, including apoptosis, through transcription-dependent and transcription-independent mechanisms. On the one hand, nuclear p53 transcriptionally activates the expression of a myriad of pro-apoptotic BCL-2 family genes, such as NOXA, PUMA, BID, BAD, BIK, BAX, etc., whereas it inactivates the expression of anti-apoptotic BCL-2, BCL-XL, and MCL1, leading to mitochondrial apoptosis. On the other hand, cytoplasmic p53 also promotes mitochondrial apoptosis by directly associating with multiple BCL-2 family proteins in the mitochondria. Apoptosis-related protein in TGF-β signaling pathway (ARTS), a mitochondria-localized pro-apoptotic protein encoded by an alternative spliced variant of the SEPT4 gene, triggers apoptosis by facilitating proteasomal degradation of BCL-2 and XIAP upon pro-apoptotic stimuli. We recently identified SEPT4/ARTS as a new p53 target gene in response to genotoxic stress. ARTS in turn binds to p53, drives its mitochondrial localization, and enhances the interaction between p53 and BCL-XL, thereby promoting mitochondrial apoptosis. This review will illustrate the mechanisms of p53-induced mitochondrial apoptosis, offer some recently discovered new insights into the functions of ARTS in regulating mitochondrial cell death, and discuss the clinical significance of ARTS in cancer and non-cancer diseases.