Lysosomal destabilization in p53-induced apoptosis.
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.
Yuan
Xi-Ming
XM
Pathology II, Linköping University, Linköping 581 85, Sweden. yuan.ximing@inr.liu.se
Li
Wei
W
Dalen
Helge
H
Lotem
Joseph
J
Kama
Rachel
R
Sachs
Leo
L
Brunk
Ulf T
UT
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003574:Cytochrome c Group / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013696:Temperature; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism*
D003574:Cytochrome c Group; D015850:Interleukin-6; D011994:Recombinant Proteins; D015842:Serine Proteinase Inhibitors; D016159:Tumor Suppressor Protein p53; D014108:Tosylphenylalanyl Chloromethyl Ketone; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases