PMID- 11756562 OWN - NLM STAT- MEDLINE DCOM- 20020129 LR - 20220227 IS - 0270-7306 (Print) IS - 1098-5549 (Electronic) IS - 0270-7306 (Linking) VI - 22 IP - 2 DP - 2002 Jan TI - Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation. PG - 680-91 AB - 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. FAU - Suhara, Toshimitsu AU - Suhara T AD - Division of Cardiovascular Research, St. Elizabeth's Medical Center of Boston, Massachusetts 02135, USA. FAU - Kim, Hyo-Soo AU - Kim HS FAU - Kirshenbaum, Lorrie A AU - Kirshenbaum LA FAU - Walsh, Kenneth AU - Walsh K LA - eng GR - HL50692/HL/NHLBI NIH HHS/United States GR - HD23681/HD/NICHD NIH HHS/United States GR - R01 AG017241/AG/NIA NIH HHS/United States GR - AR40197/AR/NIAMS NIH HHS/United States GR - R01 AG015052/AG/NIA NIH HHS/United States GR - AG15052/AG/NIA NIH HHS/United States GR - R37 AG015052/AG/NIA NIH HHS/United States GR - P01 HD023681/HD/NICHD NIH HHS/United States GR - R01 AR040197/AR/NIAMS NIH HHS/United States GR - AG17241/AG/NIA NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, P.H.S. PL - United States TA - Mol Cell Biol JT - Molecular and cellular biology JID - 8109087 RN - 0 (Androstadienes) RN - 0 (DNA-Binding Proteins) RN - 0 (FASLG protein, human) RN - 0 (FOXO1 protein, human) RN - 0 (FOXO3 protein, human) RN - 0 (Fas Ligand Protein) RN - 0 (Forkhead Box Protein O1) RN - 0 (Forkhead Box Protein O3) RN - 0 (Forkhead Transcription Factors) RN - 0 (Membrane Glycoproteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Transcription Factors) RN - EC 2.7.11.1 (AKT1 protein, human) RN - EC 2.7.11.1 (Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 3.4.22.- (CASP3 protein, human) RN - EC 3.4.22.- (CASP9 protein, human) RN - EC 3.4.22.- (Caspase 3) RN - EC 3.4.22.- (Caspase 9) RN - EC 3.4.22.- (Caspases) RN - XVA4O219QW (Wortmannin) SB - IM MH - Androstadienes/pharmacology MH - Apoptosis/drug effects MH - Caspase 3 MH - Caspase 9 MH - Caspases/*metabolism MH - Cells, Cultured MH - DNA-Binding Proteins/metabolism MH - Enzyme Activation MH - Fas Ligand Protein MH - Forkhead Box Protein O1 MH - Forkhead Box Protein O3 MH - Forkhead Transcription Factors MH - Humans MH - JNK Mitogen-Activated Protein Kinases MH - Jurkat Cells MH - Membrane Glycoproteins/antagonists & inhibitors/genetics/*metabolism MH - Mitogen-Activated Protein Kinases/*metabolism MH - Models, Biological MH - Muscle, Smooth, Vascular/cytology/drug effects/metabolism MH - *Protein Serine-Threonine Kinases MH - Proto-Oncogene Proteins/*metabolism MH - Proto-Oncogene Proteins c-akt MH - Signal Transduction/drug effects MH - Transcription Factors/metabolism MH - Wortmannin PMC - PMC139747 EDAT- 2002/01/05 10:00 MHDA- 2002/01/30 10:01 PMCR- 2002/01/01 CRDT- 2002/01/05 10:00 PHST- 2002/01/05 10:00 [pubmed] PHST- 2002/01/30 10:01 [medline] PHST- 2002/01/05 10:00 [entrez] PHST- 2002/01/01 00:00 [pmc-release] AID - 1106 [pii] AID - 10.1128/MCB.22.2.680-691.2002 [doi] PST - ppublish SO - Mol Cell Biol. 2002 Jan;22(2):680-91. doi: 10.1128/MCB.22.2.680-691.2002.