Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation

Abstract

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.