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Lysosomal destabilization in p53-induced apoptosis
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. (Medicin)
Linköping University, Department of Medicine and Health Sciences, Pharmacology. Linköping University, Faculty of Health Sciences. (Medicin)
Deparment of Pathology, The Gade Institute, University of Bergen, Bergen N-5021, Norway.
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
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2002 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 99, no 9, 6286-6291 p.Article in journal (Refereed) Published
Abstract [en]

The tumor suppressor wild-type p53 can induce apoptosis. M1-t-p53 myeloid leukemic cells have a temperature-sensitive p53 protein that changes its conformation to wild-type p53 after transfer from 37 degrees C to 32 degrees C. We have now found that these cells showed an early lysosomal rupture after transfer to 32 degrees C. Mitochondrial damage, including decreased membrane potential and release of cytochrome c, and the appearance of apoptotic cells occurred later. Lysosomal rupture, mitochondrial damage, and apoptosis were all inhibited by the cytokine IL-6. Some other compounds can also inhibit apoptosis induced by p53. The protease inhibitor N-tosyl-l-phenylalanine chloromethyl ketone inhibited the decrease in mitochondrial membrane potential and cytochrome c release, the Ca(2+)-ATPase inhibitor thapsigargin inhibited only cytochrome c release, and the antioxidant butylated hydroxyanisole inhibited only the decrease in mitochondrial membrane potential. In contrast to IL-6, these other compounds that inhibited some of the later occurring mitochondrial damage did not inhibit the earlier p53-induced lysosomal damage. The results indicate that apoptosis is induced by p53 through a lysosomal-mitochondrial pathway that is initiated by lysosomal destabilization, and that this pathway can be dissected by using different apoptosis inhibitors. These findings on the induction of p53-induced lysosomal destabilization can also help to formulate new therapies for diseases with apoptotic disorders.

Place, publisher, year, edition, pages
2002. Vol. 99, no 9, 6286-6291 p.
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Medical and Health Sciences
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URN: urn:nbn:se:liu:diva-56716DOI: 10.1073/pnas.092135599ISI: 000175377800097PubMedID: 11959917OAI: oai:DiVA.org:liu-56716DiVA: diva2:321576
Available from: 2010-06-01 Created: 2010-06-01 Last updated: 2017-12-12

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Yuan, Xi-MingLi, WeiBrunk, Ulf T.

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