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Protein kinase C regulates Fas (CD95/APO-1) expression
1Department of Immunology, Jerome H. Holland Laboratory, American Red Cross, Rockville, MD 20855, USA.
Abstract:
Fas (CD95/APO-1) is a transmembrane protein of the TNF/neuron growth factor receptor family. Ligation of Fas by specific Abs or Fas ligand (FasL/CD95 ligand) induces rapid apoptotic cell death in a variety of cell types. Despite progress in understanding the death signals transduced from Fas, very little is known with regard to the mechanisms by which Fas expression is regulated. Using our previously established murine T cell hybridoma model A1.1, we show that specific protein kinase C (PKC) inhibitors could block activation-induced Fas expression and apoptosis. The activation of PKC with PMA or 1-oleoyl-2-acetyl-sn-glycerol could mimic the TCR signal by inducing the expression of Fas but not FasL. PKC-dependent Fas expression was also observed in several murine and human tumor cell lines. Since the inhibition of Ca2+ redistribution by an inhibitor of intracellular Ca2+ mobilization, 8-(diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride, inhibited TCR-induced FasL but not Fas, the expression of Fas appears to be independent of Ca2+ mobilization. Significantly, expression of the newly identified Fas-regulatory gene, TDAG51, was found to be dependent upon the activity of PKC. PKC activation only induced Fas expression in cells expressing wild-type TDAG51. Thus, Fas expression is likely mediated by PKC through TDAG51.
Insights
Protein Kinase C (PKC) activation regulates Fas expression, a key protein in apoptosis. PKC influences Fas expression through the TDAG51 gene, independent of calcium signaling.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- Fas (CD95/APO-1) is a TNF receptor family member inducing apoptosis upon ligation.
- Mechanisms regulating Fas expression remain largely unknown.
- Understanding Fas regulation is crucial for controlling cell death.
Purpose of the Study:
- To investigate the role of Protein Kinase C (PKC) in regulating Fas expression.
- To elucidate the signaling pathways involved in activation-induced Fas expression.
- To identify novel genes involved in Fas regulation.
Main Methods:
- Utilized a murine T cell hybridoma model (A1.1).
- Employed PKC inhibitors and activators (PMA, 1-oleoyl-2-acetyl-sn-glycerol).
- Assessed Fas and FasL expression, calcium mobilization, and TDAG51 gene expression.
Main Results:
- PKC inhibitors blocked activation-induced Fas expression and apoptosis.
- PKC activation mimicked TCR signals, inducing Fas but not FasL expression.
- Fas expression was independent of calcium mobilization but dependent on TDAG51 expression.
- PKC activation induced Fas expression only in cells with wild-type TDAG51.
Conclusions:
- Fas expression is regulated by PKC activity.
- PKC mediates Fas expression, likely through the TDAG51 gene.
- This pathway offers potential targets for modulating apoptosis.