Bax activation and translocation to mitochondria mediate EGF-induced programmed cell death.
The ErbB family of receptor tyrosine kinases is involved in the regulation of cell proliferation, differentiation and apoptosis. Previous studies indicate that cells expressing elevated levels of the EGFR and ErbB-2 undergo programmed cell death in response to EGF or other EGFR ligands. However, the detailed mechanisms of EGF-induced apoptosis are unclear. This report demonstrates that in the cells undergoing EGF-dependent apoptosis Bax changes its conformation and forms multimeric aggregates, which accumulate on the mitochondrial membrane. Bax activation and translocation to the mitochondria induces a loss of mitochondrial transmembrane potential and cell death. Also, during EGF-induced apoptosis there is downregulation of Bcl-xL, an anti-apoptotic protein. Expression of Bcl-xL in cells susceptible to EGF-dependent apoptosis prevents cell death. The data indicate that addition of EGF does not result in a significant release of cytochrome c from mitochondria and EGF-induced apoptosis is mainly caspase independent.
Tikhomirov
Oleg
O
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
Carpenter
Graham
G
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045304:Cytochromes c / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis* / Q000235:genetics; D051020:bcl-X Protein / Q000096:biosynthesis / Q000235:genetics
D020169:Caspases; D045304:Cytochromes c; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein