Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death |
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Authors: | Wei M C Zong W X Cheng E H Lindsten T Panoutsakopoulou V Ross A J Roth K A MacGregor G R Thompson C B Korsmeyer S J |
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Institution: | Howard Hughes Medical Institute, Departments of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA 02115, USA. |
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Abstract: | Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family member, triggers the homooligomerization of "multidomain" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for cell death in response to diverse stimuli. |
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