AKT controls human first trimester trophoblast cell sensitivity to FAS-mediated apoptosis by regulating XIAP expression.
The PIK3/AKT pathway plays an important role in both the inhibition of the apoptotic cascade and the promotion of cell growth and proliferation. Multiple apoptosis-related targets of phosphatidylinositide 3-kinase (PIK3) and protein kinase B (AKT) have been identified, including the antiapoptotic protein XIAP. By phosphorylating XIAP, AKT was previously shown to prevent the ubiquitinization and degradation of XIAP. First-trimester trophoblast cells express high levels of XIAP, which protects them from certain apoptotic stimuli. In this study, we determine that the inhibition of the PIK3/AKT pathway induces XIAP inactivation and the activation of caspase 3 in first-trimester trophoblast cells. Using a specific AKT inhibitor and a XIAP mutant construct, which mimics the AKT phosphorylated form of XIAP, we also demonstrate that these effects are dependent on the phosphorylation of XIAP by AKT. Finally, we show that the selective inhibition of AKT renders normally resistant first-trimester trophoblast cells sensitive to FAS-mediated apoptosis by regulating XIAP expression. Our findings may provide a link between AKT, XIAP, and the regulation of the FAS apoptotic cascade in first-trimester trophoblast cells and contribute to our current knowledge of the molecular mechanisms mediating normal trophoblast physiology during pregnancy.
Straszewski-Chavez
Shawn L
SL
Department of Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Abrahams
Vikki M
VM
Aldo
Paula B
PB
Romero
Roberto
R
Mor
Gil
G
D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002747:Chlorpropamide / Q000031:analogs & derivatives; D002867:Chromones; D015536:Down-Regulation; D005260:Female; D006801:Humans; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014327:Trophoblasts / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*; D000096926:Benzenesulfonamides
D053148:Caspase 3; D002747:Chlorpropamide; D002867:Chromones; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051636:X-Linked Inhibitor of Apoptosis Protein; D019014:fas Receptor; C111224:API 2; D000096926:Benzenesulfonamides; C491901:FAS protein, human; C496866:XIAP protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one