Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation.
Fas and Fas ligand (FasL) expression has been detected in chronic vascular lesions, and Fas-mediated apoptosis of vascular smooth muscle cells (VSMC) may influence the integrity of the atherosclerotic plaque. Here we report that FasL is not expressed by normal VSMC, but its expression is upregulated by stresses that induce apoptosis, including serum deprivation, exposure to the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, and ablation of Akt signaling. Conversely, constitutive activation of Akt signaling diminished FasL expression in VSMC cultures exposed to low-mitogen media or wortmannin. Under conditions of suppressed PI 3-kinase/Akt signaling, VSMC apoptosis was partially inhibited by treatment with neutralizing antibody against FasL. Suppression of Akt signaling increased the activity of c-Jun N-terminal kinase, and transduction of dominant-negative c-Jun inhibited FasL induction under these conditions. Diminished Akt signaling promoted the cleavage of caspase 3, and both caspase 3 cleavage and FasL induction were inhibited by transduction of dominant-negative caspase 9 or the caspase 8 inhibitor CrmA. Similarly, induction of FasL by the Akt-regulated forkhead transcription factor FKHRL1 was dependent upon caspase and c-Jun activation. Taken together, these results indicate that the sequential activation of caspase 3 and c-Jun participates in the induction of FasL under conditions of suppressed Akt signaling or FKHRL1 activation and that FasL participates in a positive-feedback loop to promote cell death under conditions of cellular stress.
Suhara
Toshimitsu
T
Division of Cardiovascular Research, St. Elizabeth's Medical Center of Boston, Massachusetts 02135, USA.
Kim
Hyo-Soo
HS
Kirshenbaum
Lorrie A
LA
Walsh
Kenneth
K
D000730:Androstadienes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D053222:Fas Ligand Protein; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases; D000077191:Wortmannin