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Fungal metabolite FR901228 inhibits c-Myc and Fas ligand expression
1Department of Immunology, Jerome H Holland Laboratory, American Red Cross, Rockville, Maryland 20855, USA.
Abstract:
Activation of T lymphocytes often leads to cellular activation, production of cytokines, entry into cell cycle, and expression of Fas (CD95) and Fas ligand (FasL). Although it is well established that the interaction of Fas and FasL results in apoptosis, mechanisms for regulated expression of Fas and FasL are unclear. Our previous work with antisense oligodeoxynucleotides suggested that the protooncogene c-myc is obligatory for activation-induced apoptosis. To study the relationship between c-myc and the Fas/FasL expression, we employed the antisense method and a newly identified fungal metabolite, FR901228, which has been shown to specifically inhibit expression of c-myc in fibroblasts. We found that FR901228 could effectively block activation-induced apoptosis in T cell hybridomas and this was correlated with its specific inhibition of c-myc expression. Both FR901228 and antisense oligodeoxynucleotide to c-myc had similar effect in inhibiting FasL expression. These treatments did not affect activation-induced production of IL-2, nor the expression of Fas. In addition, FR901228 inhibited the expression of FasL in 3T3 fibroblasts, but not these transfected with c-myc, supporting a specific role of c-myc in this process. Thus, c-Myc plays a fundamental role in the regulation of the expression of FasL, but not Fas and IL-2. Our data further defined the requirement of c-Myc in activation-induced apoptosis in T cells.
Insights
The protooncogene c-Myc is crucial for T cell activation-induced apoptosis by regulating Fas ligand (FasL) expression. This study reveals c-Myc
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- T lymphocyte activation triggers cellular responses including cytokine production and apoptosis via Fas/FasL interaction.
- Mechanisms regulating Fas and Fas ligand (FasL) expression during T cell activation are not fully understood.
- Previous research indicated the protooncogene c-myc is essential for activation-induced apoptosis.
Purpose of the Study:
- To investigate the relationship between c-myc and the expression of Fas/FasL during T cell activation.
- To elucidate the role of c-Myc in regulating activation-induced apoptosis in T cells.
Main Methods:
- Utilized antisense oligodeoxynucleotides to inhibit c-myc expression.
- Employed the fungal metabolite FR901228, a specific c-myc inhibitor.
- Assessed T cell hybridomas and 3T3 fibroblasts for apoptosis, cytokine production (IL-2), and expression of Fas and FasL.
Main Results:
- FR901228 and antisense c-myc oligodeoxynucleotides blocked activation-induced apoptosis in T cells.
- These treatments specifically inhibited c-myc and FasL expression, but not Fas or IL-2 production.
- FR901228 inhibited FasL expression in fibroblasts, with this effect abolished in c-myc-transfected cells, confirming c-Myc's specific role.
Conclusions:
- c-Myc plays a fundamental role in regulating FasL expression, a key mediator of apoptosis.
- c-Myc is essential for activation-induced apoptosis in T cells, acting upstream of FasL.
- The findings define a critical role for c-Myc in the Fas/FasL pathway during T cell activation.