title: Dynamic roles of p53-mediated metabolic activities in ROS-induced stress responses.
abstract: The p53 tumor suppressor is a multifaceted polypeptide that impedes tumorigenesis by regulating a diverse array of cellular processes. Triggered by a wide variety of stress stimuli, p53 transcriptionally regulates genes involved in the canonical tumor suppression pathways of apoptosis, cell-cycle arrest, and senescence. We recently discovered a novel mechanism whereby p53 inhibits cystine uptake through repression of the SLC7A11 gene to mediate ferroptosis. Importantly, this p53-SLC7A11 axis is preserved in the p53(3KR) mutant, and contributes to its ability to suppress tumorigenesis in the absence of the classical tumor suppression mechanisms. Here, we report that wild type p53 can induce both apoptosis and ferroptosis upon reactive oxygen species (ROS)-induced stress. Furthermore, we demonstrate that p53's functional N-terminal domain is required for its capacity to regulate oxidative stress responses and ferroptosis. Notably, activated p53 dynamically modulates intracellular ROS, causing an initial reduction and a subsequent increase of ROS levels. Taken together, these data implicate ferroptosis as an additional component of the cell death program induced by wild type p53 in human cancer cells, and reveal a complex and dynamic role of p53 in oxidative stress responses.
authors.affiliation: a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA.
authors.forename: Le
authors.initials: L
authors.lastname: Jiang
authors.affiliation: a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA.
authors.forename: Justin H
authors.initials: JH
authors.lastname: Hickman
authors.affiliation: a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA.
authors.forename: Shang-Jui
authors.initials: SJ
authors.lastname: Wang
authors.affiliation: a Institute for Cancer Genetics and Department of Pathology and Cell Biology; College of Physicians & Surgeons; Columbia University ; New York , NY USA.|b Herbert Irving Comprehensive Cancer Center; College of Physicians & Surgeons; Columbia University ; New York , NY USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016923:Cell Death; D045744:Cell Line, Tumor; D006801:Humans; D007501:Iron / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000494:pharmacology*; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000502:physiology*
chemical_list: D027182:Amino Acid Transport System y+; D017382:Reactive Oxygen Species; C118895:SLC7A11 protein, human; D016159:Tumor Suppressor Protein p53; D007501:Iron
keywords: ROS; SLC7A11; ferroptosis; p53; transcription