TY - JOUR
T1 - Protection of CD95-mediated apoptosis by activation of phosphatidylinositide 3-kinase and protein kinase B
AU - Häusler, Peter
AU - Papoff, Giuliana
AU - Eramo, Adrians
AU - Reif, Karin
AU - Cantrell, Doreen A.
AU - Ruberti, Giovina
PY - 1998/1
Y1 - 1998/1
N2 - Apoptosis may be triggered, in a variety of tissues, by interaction of the cell surface molecule CD95 with its specific ligand, CD95L. CD95 plays a physiological role in the regulation of the immune response; furthermore, alterations in CD95/CD95L function may contribute to the pathogenesis of a number of human diseases, including cancer, autoimmune diseases and viral infections. Many cells that express CD95, however, are not susceptible to CD95-mediated apoptosis. It is therefore important to identify the mechanisms that counteract the CD95 apoptotic process that are still poorly understood. Growth factors and lymphokines such as interleukin (IL)-4 that counteract CD95-mediated apoptosis may activate phosphatidylinositide 3-kinase (PI 3-kinase). We therefore used two different approaches to investigate the role of PI 3-kinase on CD95-mediated apoptosis. First we tested the effect of two pharmacological PI 3-kinase inhibitors, wortmannin and LY294002, on CD95 agonistic antibody-induced apoptosis in three different cell lines. Second, we co-expressed in COS7 cells CD95 with constitutively active PI 3-kinase. Results of both approaches indicate that active PI 3-kinase effectively protects against CD95-mediated apoptosis. Furthermore we extended our studies on the CD95 downstream mediator, FADD, and on the PI 3-kinase downstream mediator, the serine/threonine protein kinase PKB, using the co-expression approach in COS7 cells. We provide evidence that apoptosis induced by triggering the CD95 cell death receptor is counteracted by PI 3-kinase activation; moreover, PKB but not p70(S6K) represents the relevant downstream target of PI 3-kinase signaling.
AB - Apoptosis may be triggered, in a variety of tissues, by interaction of the cell surface molecule CD95 with its specific ligand, CD95L. CD95 plays a physiological role in the regulation of the immune response; furthermore, alterations in CD95/CD95L function may contribute to the pathogenesis of a number of human diseases, including cancer, autoimmune diseases and viral infections. Many cells that express CD95, however, are not susceptible to CD95-mediated apoptosis. It is therefore important to identify the mechanisms that counteract the CD95 apoptotic process that are still poorly understood. Growth factors and lymphokines such as interleukin (IL)-4 that counteract CD95-mediated apoptosis may activate phosphatidylinositide 3-kinase (PI 3-kinase). We therefore used two different approaches to investigate the role of PI 3-kinase on CD95-mediated apoptosis. First we tested the effect of two pharmacological PI 3-kinase inhibitors, wortmannin and LY294002, on CD95 agonistic antibody-induced apoptosis in three different cell lines. Second, we co-expressed in COS7 cells CD95 with constitutively active PI 3-kinase. Results of both approaches indicate that active PI 3-kinase effectively protects against CD95-mediated apoptosis. Furthermore we extended our studies on the CD95 downstream mediator, FADD, and on the PI 3-kinase downstream mediator, the serine/threonine protein kinase PKB, using the co-expression approach in COS7 cells. We provide evidence that apoptosis induced by triggering the CD95 cell death receptor is counteracted by PI 3-kinase activation; moreover, PKB but not p70(S6K) represents the relevant downstream target of PI 3-kinase signaling.
KW - Apoptosis
KW - CD95
KW - Phosphatidylinositide 3-kinase
KW - Protein kinase B
UR - http://www.scopus.com/inward/record.url?scp=0039058167&partnerID=8YFLogxK
U2 - 10.1002/(SICI)1521-4141(199801)28:01<57::AID-IMMU57>3.0.CO;2-8
DO - 10.1002/(SICI)1521-4141(199801)28:01<57::AID-IMMU57>3.0.CO;2-8
M3 - Article
C2 - 9485186
AN - SCOPUS:0039058167
SN - 0014-2980
VL - 28
SP - 57
EP - 69
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 1
ER -