Activation of mitochondrial Raf-1 is involved in the antiapoptotic effects of Akt.
The Akt serine/threonine kinase is required for the survival of many cell types and for transformation of hematopoietic cells by the BCR/ABL oncogenic tyrosine kinase. Analysis of the potential mechanisms whereby Akt promotes survival of hematopoietic cells revealed that it induced the activity of plasma membrane and mitochondrial Raf-1 in a Ras-independent, but PKC-dependent manner. Inhibition of plasma membrane Raf-1-dependent mitogen-activated protein kinase activity had no effect on the enhanced survival of cells expressing Akt. By contrast, suppression of mitochondrial Raf-1 enzymatic activity by expression of a mitochondria-targeted Raf-1 dominant-negative mutant rendered Akt-expressing cells susceptible to apoptosis induced by growth factor deprivation and was accompanied by inhibition of BAD, but not mitogen-activated protein kinase, phosphorylation. Together, these data indicate that PKC-dependent activation of Raf-1 plays an important role in Akt-dependent antiapoptotic effects.
Majewski
M
M
Department of Microbiology and Immunology, Kimmel Cancer Institute, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Nieborowska-Skorska
M
M
Salomoni
P
P
Slupianek
A
A
Reiss
K
K
Trotta
R
R
Calabretta
B
B
Skorski
T
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D051058:Oncogene Protein v-akt; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000502:physiology*
D015682:Retroviridae Proteins, Oncogenic; D051058:Oncogene Protein v-akt; D019908:Proto-Oncogene Proteins c-raf