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Cell death induced by 7-oxysterols via lysosomal and mitochondrial pathways is p53-dependent
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
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2012 (English)In: Free Radical Biology & Medicine, ISSN 0891-5849, E-ISSN 1873-4596, Vol. 53, no 11, 2054-2061 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Elsevier , 2012. Vol. 53, no 11, 2054-2061 p.
Keyword [en]
Apoptosis, Atherosclerosis, Bax, Lysosomes, Mitochondria, Oxidative stress, Free radicals
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-86892DOI: 10.1016/j.freeradbiomed.2012.09.007ISI: 000312058300007OAI: oai:DiVA.org:liu-86892DiVA: diva2:583045
Note

Funding Agencies|Swedish Heart Lung Foundation||Torsten and Ragnar Soderbergs Foundation||Stroke Foundation||Olle Engkvist Foundation||Swedish Gamla Tjanarinnor Foundation||Linkoping University||Linkoping University Hospital||

Available from: 2013-01-07 Created: 2013-01-07 Last updated: 2017-12-06

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Li, WeiLaskar, AmitSultana, NargisOsman, EhabYuan, Ximing

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