title: Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent.
abstract: Oxysterol accumulation and p53 expression mainly in macrophages have been associated with cell death and necrotic core formation in human atheroma progression. Oxidative stress and lysosomal membrane permeabilization (LMP) in macrophages are important causes of macrophage apoptosis. However, it is not understood how p53 and oxysterols interact in the process. We show here that 7-oxysterols induce endogenous full-length p53 and phospho-p53 (p53-Ser15) in both nucleus and cytoplasm of THP1 and J774 cells, which is followed by cellular oxidative stress and apoptotic cell death. The role of p53 in 7-oxysterol-mediated cell death is further investigated in temperature sensitive p53-transfected (M1-t-p53) and in p53-deficient (M1) cells. These results reveal that 7-oxysterols induce induction and nuclear translocation of p53 in M1-t-p53 cells, which in turn enhances LMP, mitochondrial translocation of Bax, mitochondrial membrane permeabilization, cytosolic release of cytochrome c, and cell death. Most importantly, the above effects of 7-oxysterols were not observed in p53-deficient M1 cells. The findings reveal that 7-oxysterol-induced cell death occurs via p53-dependent pathways. Subsequent p53 nuclear translocation and induction of wild-type and phosphorylated p53 are early steps in oxysterol-induced lysosomal-mitochondrial pathways involved in cell death.
authors.affiliation: Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping SE-581 85, Sweden. wei.li@liu.se
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Amit
authors.initials: A
authors.lastname: Laskar
authors.forename: Nargis
authors.initials: N
authors.lastname: Sultana
authors.forename: Ehab
authors.initials: E
authors.lastname: Osman
authors.forename: Moumita
authors.initials: M
authors.lastname: Ghosh
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Li
authors.forename: Xi-Ming
authors.initials: XM
authors.lastname: Yuan
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D007653:Ketocholesterols / Q000494:pharmacology* / Q000502:physiology; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000502:physiology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009336:Necrosis; D018384:Oxidative Stress; D010539:Permeability; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C011724:cholest-5-en-3 beta,7 alpha-diol; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C003001:7-ketocholesterol