Negative regulation of mitochondrial VDAC channels by C-Raf kinase.
BACKGROUND
Growth of cancer cells results from the disturbance of positive and negative growth control mechanisms and the prolonged survival of these genetically altered cells due to the failure of cellular suicide programs. Genetic and biochemical approaches have identified Raf family serine/threonine kinases B-Raf and C-Raf as major mediators of cell survival. C-Raf cooperates with Bcl-2/Bcl-XL in suppression of apoptosis by a mechanism that involves targeting of C-Raf to the outer mitochondrial membrane and inactivation of the pro-apoptotic protein Bad. However, apoptosis suppression by C-Raf also occurs in cells lacking expression of Bad or Bcl-2.


RESULTS
Here we show that even in the absence of Bcl-2/Bcl-XL, mitochondria-targeted C-Raf inhibits cytochrome c release and caspase activation induced by growth factor withdrawal. To clarify the mechanism of Bcl-2 independent survival control by C-Raf at the mitochondria a search for novel mitochondrial targets was undertaken that identified voltage-dependent anion channel (VDAC), a mitochondrial protein (porin) involved in exchange of metabolites for oxidative phosphorylation. C-Raf forms a complex with VDAC in vivo and blocks reconstitution of VDAC channels in planar bilayer membranes in vitro.


CONCLUSIONS
We propose that this interaction may be responsible for the Raf-induced inhibition of cytochrome c release from mitochondria in growth factor starved cells. Moreover, C-Raf kinase-induced VDAC inhibition may regulate the metabolic function of mitochondria and mediate the switch to aerobic glycolysis that is common to cancer cells.
Le Mellay
Véronique
V
Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, 97078 Würzburg, Germany. lemellay@univ-montp2.fr
Troppmair
Jakob
J
Benz
Roland
R
Rapp
Ulf R
UR
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism; D007700:Kinetics; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D018272:Porins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology*; D050994:Voltage-Dependent Anion Channels
D003574:Cytochrome c Group; D018272:Porins; D050994:Voltage-Dependent Anion Channels; D019908:Proto-Oncogene Proteins c-raf; D020169:Caspases