Evidence that bcl-2 is the target of three photosensitizers that induce a rapid apoptotic response.
We originally proposed that the subcellular target for one class of photosensitizing agents was the mitochondrion. This classification was based on effects that occur within minutes of irradiation of photosensitized cells: rapid loss of the mitochondrial membrane potential (delta psi m), release of cytochrome c into the cytosol and activation of caspase-3. These effects were followed by the appearance of an apoptotic morphology within 30-90 min. Fluorescence localization studies on three sensitizers initially classified as 'mitochondrial' revealed that these agents bind to a variety of intracellular membranes. The earliest detectable effect of photodamage is the selective loss of the antiapoptotic protein bcl-2 leaving the proapoptotic protein bax undamaged. Bcl-2 photodamage can be detected directly after irradiation of cells at 10 degrees C. Subsequent warming of cultures to 37 degrees C results in loss of delta psi m, release of cytochrome c and activation of caspase-3. The latter appears to amplify the other two effects. Based on results reported here we propose that the apoptotic response to these photosensitizers is derived from selective photodamage to the antiapoptotic protein bcl-2 while leaving the proapoptotic protein bax unaffected.
Kessel
D
D
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA. dhkessel@med.wayne.edu
Castelli
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D007939:Leukemia L1210 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018462:Photobiology; D017319:Photosensitizing Agents / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000528:radiation effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects* / Q000528:radiation effects; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D017319:Photosensitizing Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein