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Expression of Fas ligand in activated T cells is regulated by c-Myc
T Brunner1, S Kasibhatla, M J Pinkoski
1Division of Immunopathology, Institute for Pathology, University of Berne, 3010 Berne, Switzerland.
Abstract:
The transcription factor c-Myc is important for the control of cell cycle progression, neoplasia, and apoptotic cell death. c-Myc dimerizes with its partner Max to form an active transcription factor complex. Little is known, however, about the transcriptional targets of c-Myc and their roles in c-Myc-induced cell death. Here we demonstrate that T cell activation-induced expression of Fas ligand (FasL, CD95-L, APO-1-L), which can induce apoptotic cell death in many different cell types, is regulated by c-Myc. Down-modulation of c-Myc protein via antisense oligonucleotides blocked activation-induced FasL mRNA and protein expression and functional FasL expression in activated T cells and T cell lines. Further, FasL promoter activity in T cells is driven by overexpression of c-Myc and inhibited by expression of dominant-negative mutants of c-Myc and Max. Our findings indicate that c-Myc controls apoptotic cell death in T cells through regulation of FasL expression.
Insights
The transcription factor c-Myc regulates Fas ligand (FasL) expression in T cells, controlling apoptotic cell death. This study reveals c-Myc
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- The transcription factor c-Myc is crucial for cell cycle control, neoplasia, and apoptosis.
- c-Myc partners with Max to form an active transcription factor complex.
- Transcriptional targets of c-Myc and their roles in c-Myc-induced cell death are not well understood.
Purpose of the Study:
- To investigate the role of c-Myc in regulating T cell activation-induced expression of Fas ligand (FasL).
- To elucidate the mechanism by which c-Myc controls apoptotic cell death in T cells.
Main Methods:
- Down-modulation of c-Myc protein using antisense oligonucleotides.
- Analysis of FasL mRNA, protein, and functional expression in activated T cells and T cell lines.
- FasL promoter activity assays with c-Myc overexpression and dominant-negative mutants of c-Myc and Max.
Main Results:
- Down-modulation of c-Myc blocked activation-induced FasL expression (mRNA, protein, and functional).
- Overexpression of c-Myc enhanced FasL promoter activity in T cells.
- Dominant-negative mutants of c-Myc and Max inhibited FasL promoter activity.
Conclusions:
- c-Myc regulates T cell activation-induced Fas ligand (FasL) expression.
- c-Myc controls apoptotic cell death in T cells through the regulation of FasL expression.