NDLI: Lysosomal destabilization in p53-induced apoptosis.

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Lysosomal destabilization in p53-induced apoptosis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sachs, Leo Lotem, Joseph Dalen, Helge Li, Wei Brunk, Ulf T. Kama, Rachel Yuan, Xi-ming
Description	Author Affiliation: Yuan XM ( Pathology II, Linköping University, Linköping 581 85, Sweden. yuan.ximing@inr.liu.se);
Abstract	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.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	9
Volume Number	99
Language	English
Publisher	National Academy of Sciences
Publisher Date	2002-05-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Apoptosis Lysosomes Metabolism Tumor Suppressor Protein P53 Animals Blotting, Western Calcium-Transporting ATPases Cell Membrane Cells, Cultured Cytochrome c Group Flow Cytometry Interleukin-6 Membrane Potentials Mice Microscopy, Electron Mitochondria Models, Biological Protein Conformation Recombinant Proteins Serine Proteinase Inhibitors Pharmacology Temperature Thapsigargin Time Factors Tosylphenylalanyl Chloromethyl Ketone Chemistry Research Support, Non-U.S. Gov't Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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