期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 24, 期 2, 页码 730-740出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.24.2.730-740.2004
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资金
- NCI NIH HHS [R01 CA090764, CA 90764] Funding Source: Medline
- NIA NIH HHS [R01 AG016927, AG 16927] Funding Source: Medline
- NIDDK NIH HHS [T32 DK007739, T32 DK 007739-06] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA090764] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK007739] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG016927] Funding Source: NIH RePORTER
The serine/threonine kinase Akt/protein kinase B inhibits apoptosis induced by a variety of stimuli, including overexpression or activation of proapoptotic Bcl-2 family members. The precise mechanisms by which Akt prevents apoptosis are not completely understood, but Akt may function to maintain mitochondrial integrity, thereby preventing cytochrome c release following an apoptotic insult. This effect may be mediated, in part, via promotion of physical and functional interactions between mitochondria and hexokinases. Here we show that growth factor deprivation induced proteolytic cleavage of the proapoptotic Bcl-2 family member BID to yield its active truncated form, tBID. Activated Akt inhibited mitochondrial cytochrome c release and apoptosis following BID cleavage. Akt also antagonized tBID-mediated BAX activation and mitochondrial BAK oligomerization, two downstream events thought to be critical for tBID-induced apoptosis. Glucose deprivation, which impaired the ability of Akt to maintain mitochondrion-hexokinase association, prevented Akt from inhibiting BID-mediated apoptosis. Interestingly, tBID independently elicited dissociation of hexokinases from mitochondria, an effect that was antagonized by activated Akt. Ectopic expression of the amino-terminal half of hexokinase II, which is catalytically active and contains the mitochondrion-binding domain, consistently antagonized tBID-induced apoptosis. These results suggest that Akt inhibits BID-mediated apoptosis downstream of BID cleavage via promotion of mitochondrial hexokinase association and antagonism of tBID-mediated BAX and BAK activation at the mitochondria.
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