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首页> 外文期刊>Molecular and Cellular Biology >Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation
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Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-Mediated Fas Ligand Regulation

机译：Akt信号传导的抑制诱导Fas配体表达：Caspase和Jun激酶激活参与Akt介导的Fas配体调控。

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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.
机译：Fas和Fas配体（FasL）的表达已在慢性血管病变中检测到，并且Fas介导的血管平滑肌细胞（VSMC）凋亡可能影响动脉粥样硬化斑块的完整性。在这里，我们报道FasL不能由正常VSMC表达，但其表达会被诱导凋亡的应激上调，包括血清剥夺，暴露于磷脂酰肌醇3-激酶（PI 3-激酶）抑制剂渥曼青霉素和Akt信号传导消融。相反，Akt信号的组成性激活减少了暴露于低促分裂原培养基或渥曼青霉素的VSMC培养物中FasL的表达。在PI 3-激酶/ Akt信号转导被抑制的条件下，通过用抗FasL的中和抗体处理，部分抑制了VSMC凋亡。在这种情况下，抑制Akt信号转导会增加c-Jun N末端激酶的活性，显性阴性c-Jun的转导抑制FasL的诱导。减少的Akt信号传导促进了caspase 3的切割，并且caspase 3的切割和FasL的诱导均被显性阴性caspase 9或caspase 8抑制剂CrmA的转导抑制。同样，由Akt调节的叉头转录因子FKHRL1诱导FasL依赖于caspase和c-Jun激活。综上，这些结果表明，在抑制Akt信号或FKHRL1激活的条件下，胱天蛋白酶3和c-Jun的顺序激活参与FasL的诱导，并且在细胞条件下，FasL参与正反馈回路以促进细胞死亡。强调。

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