Inhibition of p53-dependent apoptosis by the KIT tyrosine kinase: regulation of mitochondrial permeability transition and reactive oxygen species generation.
The KIT protein is a receptor tyrosine kinase of the platelet derived growth factor (PDGF) receptor family which regulates haematopoiesis, melanogenesis and gut and germ cell development. KIT regulates these diverse processes, at least in part, by inhibiting apoptosis. We have previously found that KIT can suppress p53-mediated apoptosis. The mechanism by which KIT suppresses apoptosis is, however, uncharacterized. Neither is it clear how p53 induces apoptosis. In this report we find that p53-dependent apoptosis proceeds through a pathway involving depolarization of the mitochondrial electropotential gradient (delta(psi)m) and the generation of reactive oxygen species (ROS). KIT activation suppresses p53-induced apoptosis in the mouse DP16 Friend erythroleukemia cell line by preventing delta(psi)m depolarization and ROS generation. Thus, the KIT kinase prevents apoptosis by regulating mitochondrial function and cellular redox state.
Lee
J M
JM
Hamilton Regional Cancer Centre, Ontario, Canada.
D000818:Animals; D017209:Apoptosis; D004789:Enzyme Activation; D007425:Intracellular Membranes / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D010539:Permeability; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019009:Proto-Oncogene Proteins c-kit