Regulation of stress-induced nuclear protein redistribution: a new function of Bax and Bak uncoupled from Bcl-x(L)

L Lindenboim, E Blacher, C Borner, R Stein
Cell Death and Differentiation 2010, 17 (2): 346-59
Apoptosis is regulated by changes in the subcellular distribution of pro- and anti-apoptotic proteins, among which are nuclear proteins such as histone H1 (H1) and nucleophosmin (NPM). These proteins were reported to translocate to the cytosol and mitochondria, and to facilitate apoptosis in response to apoptotic stressors. The significance of this stress-induced, nuclear protein redistribution and its exact molecular mechanism are poorly understood. We show here that in mouse embryonic fibroblasts (MEFs), different apoptotic stimuli induce H1, NPM and nucleolin, but not KAP-1 nuclear/cytoplasmic redistribution, which precedes the appearance of apoptotic features. Using MEFs deficient in Bax/Bak, Apaf-1 or caspase-9, as well as caspase inhibitors, we show that this redistribution requires Bax and Bak, but neither the apoptosome nor caspases. Furthermore, the BH3 mimetic ABT-737, which acts through Bax/Bak, also stimulates nuclear protein redistribution in a Bax/Bak-dependent manner. Re-expression of Bax or Bak in Bax/Bak-deficient MEFs restores nuclear redistribution during apoptosis. This is not accompanied by Bax or Bak N-terminus exposure and is not inhibited by Bcl-x(L) overexpression. These results identify, for the first time, a function of Bax/Bak that is insensitive to inhibition by Bcl-x(L) and most likely unrelated to their canonical, pore-forming activity on mitochondria.

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