Matrix detachment induces caspase-dependent cytochrome c release from mitochondria:: inhibition by PKB/Akt but not Raf signalling

被引:121
作者
Rytömaa, M [1 ]
Lehmann, K [1 ]
Downward, J [1 ]
机构
[1] Imperial Canc Res Fund, Signal Transduct Lab, London WC2A 3PX, England
关键词
anoikis; apoptosis; Ras; Akt; PKB; Raf;
D O I
10.1038/sj.onc.1203805
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Detachment of epithelial cells from extracellular matrix results in induction of apoptosis ('anoikis') which can be blocked by expression of activated Pas or PKB/Akt. Here we show that detachment causes release of cytochrome c from mitochondria in MDCK cells, This is blocked by caspase inhibitors, suggesting a role for caspases upstream of mitochondria in the initiation of anoikis, in accord with the ability of dominant negative FADD to inhibit this form of cell death, Bulk activation of caspase-8 following detachment lags behind cytochrome c release, and is likely the result of a mitochondrial positive feed back loop. Matrix detachment also induces Bax translocation to mitochondria in a caspase-dependent manner. Expression of activated Ras or PKB/Akt blocks all the detectable events on the detachment-induced apoptosis signalling pathway, suggesting that PKB/Akt acts at an early point in the pathway, providing the signal normally generated by matrix attachment. Strong activation of Raf can also protect MDCK cells from detachment induced apoptosis, but this occurs at a point downstream of cytochrome c release from mitochondria, and is clearly distinct from the effect of PKB/Akt.
引用
收藏
页码:4461 / 4468
页数:8
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