Tags

Type your tag names separated by a space and hit enter

Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation.
Mol Cell Biol. 2002 Jan; 22(2):680-91.MC

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.

Authors+Show Affiliations

Division of Cardiovascular Research, St. Elizabeth's Medical Center of Boston, Massachusetts 02135, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11756562

Citation

Suhara, Toshimitsu, et al. "Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-mediated Fas Ligand Regulation." Molecular and Cellular Biology, vol. 22, no. 2, 2002, pp. 680-91.
Suhara T, Kim HS, Kirshenbaum LA, et al. Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation. Mol Cell Biol. 2002;22(2):680-91.
Suhara, T., Kim, H. S., Kirshenbaum, L. A., & Walsh, K. (2002). Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation. Molecular and Cellular Biology, 22(2), 680-91.
Suhara T, et al. Suppression of Akt Signaling Induces Fas Ligand Expression: Involvement of Caspase and Jun Kinase Activation in Akt-mediated Fas Ligand Regulation. Mol Cell Biol. 2002;22(2):680-91. PubMed PMID: 11756562.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation. AU - Suhara,Toshimitsu, AU - Kim,Hyo-Soo, AU - Kirshenbaum,Lorrie A, AU - Walsh,Kenneth, PY - 2002/1/5/pubmed PY - 2002/1/30/medline PY - 2002/1/5/entrez SP - 680 EP - 91 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 22 IS - 2 N2 - 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. SN - 0270-7306 UR - https://www.unboundmedicine.com/medline/citation/11756562/Suppression_of_Akt_signaling_induces_Fas_ligand_expression:_involvement_of_caspase_and_Jun_kinase_activation_in_Akt_mediated_Fas_ligand_regulation_ L2 - https://journals.asm.org/doi/10.1128/MCB.22.2.680-691.2002?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -