Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line.
Phosphatidylinositol (PI) 3-kinase has been suggested to mediate cell survival. Consistent with this possibility, apoptosis of conditionally (simian virus 40 Tts) immortalized rat hippocampal H19-7 neuronal cells was increased in response to wortmannin, an inhibitor of PI 3-kinase. Downstream effectors of PI 3-kinase include Rac1, protein kinase C, and the serine-threonine kinase Akt (protein kinase B). Here, we show that activation of Akt is one mechanism by which PI 3-kinase can mediate survival of H19-7 cells during serum deprivation or differentiation. While ectopic expression of wild-type Akt (c-Akt) does not significantly enhance survival in H19-7 cells, expression of activated forms of Akt (v-Akt or myristoylated Akt) results in enhanced survival which can be comparable to that conferred by Bcl-2. Conversely, expression of a dominant-negative mutant of Akt accelerates cell death upon serum deprivation or differentiation. Finally, the results indicate that Akt can transduce a survival signal for differentiating neuronal cells through a mechanism that is independent of induction of Bcl-2 or Bcl-XL or inhibition of Jun kinase activity.
Eves
E M
EM
Ben May Institute for Cancer Research and Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois 60637, USA. eeves@ben-may.bsd.uchicago.edu
Xiong
W
W
Bellacosa
A
A
Kennedy
S G
SG
Tsichlis
P N
PN
Rosner
M R
MR
Hay
N
N
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D016895:Culture Media, Serum-Free; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005799:Genes, Dominant; D009154:Mutation; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051381:Rats; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D000077191:Wortmannin; D051020:bcl-X Protein
D000730:Androstadienes; D016895:Culture Media, Serum-Free; D004791:Enzyme Inhibitors; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D015682:Retroviridae Proteins, Oncogenic; D000077191:Wortmannin; D051020:bcl-X Protein; C494813:Bcl2l1 protein, rat; C494920:Akt1 protein, rat