Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins

• DOI: 10.1073/pnas.0808036105
• Publication Date: 2008-12-13T01:15:50Z
• Authors: Jerry E. Chipuk; John C. Fisher; Christopher P. Di...; Richard W. Kriwacki; Tomomi Kuwana; Douglas R. Green
• Keywords: Puma; Bcl-2 Family; Bcl-2-associated X protein

Normal cellular lifespan is contingent upon preserving outer mitochondrial membrane (OMM) integrity, as permeabilization promotes apoptosis. BCL-2 family proteins control (MOMP) by regulating the activation of pro-apoptotic effector molecules, BAX and BAK. Sustainable stress induces (e.g., BID, BIM, cytosolic p53) capable directly activating and/or BAK, but these direct activators are sequestered anti-apoptotic BCL-2, BCL-xL, MCL-1). In event accumulated or marked stress, a coordinated effort between previously nascent BH3-only inhibits repertoire to promote activator protein-mediated MOMP. We examined effect ABT-737, antagonist, PUMA, protein that entire repertoire, with cells mitochondria proteins. ABT-737 PUMA cooperated MOMP apoptosis, which in absence did not influence OMM integrity survival. Our data show induction apoptosis inhibition requires "covert" levels BAK at OMM.