Genetic analysis of protein kinase B (AKT) in Drosophila.
The decision between survival and death is an important aspect of cellular regulation during development and malignancy. Central to this regulation is the process of apoptosis, which is conserved in multicellular organisms [1]. A variety of signalling cascades have been implicated in modulation of apoptosis, including the phosphatidylinositol (Pl) 3-kinase pathway. Activation of Pl 3-kinase is protective, and inhibition of this lipid kinase enhances cell death under several conditions including deregulated expression of c-Myc, neurotrophin withdrawal and anoikis [2-7]. Recently, the protective effects of Pl 3-kinase have been linked to its activation of the pleckstrin homology (PH)-domain-containing protein kinase B (PKB or AKT) [8]. PKB/AKT was identified from an oncogene, v-akt, found in a rodent T-cell lymphoma [9]. To initiate a genetic analysis of PKB, we have isolated and characterized a Drosophila PKB/AKT mutant (termed Dakt1) that exhibits ectopic apoptosis during embryogenesis as judged by induction of membrane blebbing, DNA fragmentation and macrophage infiltration. Apoptosis caused by loss of Dakt function is rescued by caspase suppression but is distinct from the previously described reaper/grim/hid functions. These data implicate Dakt1 as a cell survival gene in Drosophila, consistent with cell protection studies in mammals.
Staveley
B E
BE
Ontario Cancer Institute, Department of Medical Biophysics, University of Toronto, Canada.
Ruel
L
L
Jin
J
J
Stambolic
V
V
Mastronardi
F G
FG
Heitzler
P
P
Woodgett
J R
JR
Manoukian
A S
AS
D000818:Animals; D017209:Apoptosis; D002417:Cattle; D004330:Drosophila / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D029721:Drosophila Proteins; D005260:Female; D005786:Gene Expression Regulation; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000235:genetics; D008297:Male; D009479:Neuropeptides / Q000235:genetics; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011817:Rabbits; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D029721:Drosophila Proteins; C108880:HID protein, Drosophila; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D009479:Neuropeptides; D010455:Peptides; D011518:Proto-Oncogene Proteins; D014764:Viral Proteins; C108881:grim protein, Drosophila; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; C086973:rpr protein, Drosophila; D011505:Protein-Tyrosine Kinases; C494917:Akt1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt