Holinger JBC 274, 13298-304, 1999 Stapled alpha-helix of BCL-2 domains (SAHB) Walensky Science 305, 1466-70, 2004.

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Presentation transcript:

Holinger JBC 274, , 1999

Stapled alpha-helix of BCL-2 domains (SAHB) Walensky Science 305, , 2004

Proposed mechanism of bcl-2 pore formation

Gottlob et al., Genes Dev 2001

Akt inhibits Bax/Bak activation ( Majewski, Mol Cell Biol 2004 ) Bid displaces mitochondrial hexokinase ( ibid ) Conditions leading to loss of mitochondrial hexokinase induce apoptosis even in Bax/Bak -/- cells, and are rescued by Akt, but not Bcl-2 ( Majewski, Mol Cell 2004 )

Copyright ©2005 American Society for Clinical Investigation Levine, B. et al. J. Clin. Invest. 2005;115: The autophagy pathway and its role in cellular adaptation to nutrient deprivation

Copyright ©2005 American Society for Clinical Investigation Levine, B. et al. J. Clin. Invest. 2005;115: The molecular mechanisms of autophagy

Copyright ©2005 American Society for Clinical Investigation Levine, B. et al. J. Clin. Invest. 2005;115: Ultrastructural examples of apoptotic and autophagic cell death

Lum et al., 2005

Shimizu et al., Nat Cell Biol 2004

Autophagy is a response to nutrient stress to maintain adequate internal levels of nutrients(self-cannabilization). Role in cell death is best revealed if apoptosis is disabled (bax/bak-/-, caspase inhibitors, Bcl-xL++). In nutrient-poor conditions (or equivalent effects on mTOR signaling), autophagy maintains survival. In nutrient-rich conditions, autophagy promotes cell death in response to other types of stress.