Article

AKT controls human first trimester trophoblast cell sensitivity to FAS-mediated apoptosis by regulating XIAP expression.

Department of Molecular, Cellular, and Developmental Biology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Biology of Reproduction (impact factor: 4.01). 10/2009; 82(1):146-52. DOI:10.1095/biolreprod.109.078972 pp.146-52
Source: PubMed

ABSTRACT 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.

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    A M Martelli, P L Tazzari, G Tabellini, R Bortul, A M Billi, L Manzoli, A Ruggeri, R Conte, L Cocco
    [show abstract] [hide abstract]
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    Leukemia 10/2003; 17(9):1794-805. · 9.56 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

AKT phosphorylated form
 
AKT renders
 
antiapoptotic protein XIAP
 
apoptotic cascade
 
cell growth
 
certain apoptotic stimuli
 
current knowledge
 
FAS apoptotic cascade
 
FAS-mediated apoptosis
 
first-trimester trophoblast cells
 
molecular mechanisms mediating normal trophoblast physiology
 
phosphatidylinositide 3-kinase
 
phosphorylating XIAP
 
PIK3/AKT pathway
 
PIK3/AKT pathway induces XIAP inactivation
 
proliferation
 
protein kinase B
 
regulating XIAP expression
 
specific AKT inhibitor
 
XIAP mutant