Synergistic induction of the Fas (CD95) ligand promoter by Max and NFkappaB in human non-small lung cancer cells.
Fas (CD95/APO-1) ligand is a member of the Tumor Necrosis Factor family and a potent inducer of apoptosis. Fas ligand is expressed in activated T cells and represents a major cytotoxic effector mechanism by which T cells kill their target cells. Activation-induced Fas ligand expression in T cells is under the stringent control of various transcription factors, including nuclear factor kappaB (NFkappaB) and c-Myc/Max. There is accumulating evidence that Fas ligand is also expressed by various non-hematopoietic tumor cells, however, little is known about Fas ligand regulation in tumor cells. In this study, we have analyzed the regulation of the Fas ligand gene promoter induction in two non-small cell lung cancer cell lines, with a major focus on the role of the c-Myc/Max transcription factor. Our results revealed that inhibition of c-Myc/Max did not substantially reduce basal levels of Fas ligand promoter activity, nor did overexpression of c-Myc significantly induce promoter activity. In contrast, we observed that overexpression of Max resulted in a marked increase in basal promoter activity and synergistically enhanced phorbolester- and doxorubicin-induced NFkappaB-mediated Fas ligand promoter activity. These results were confirmed by analyzing endogenous Fas ligand transcription. We conclude that high levels of Max and stress-induced NFkappaB activation may result in elevated expression of Fas ligand in human lung cancer cells and possibly contribute to Fas ligand-associated immune escape mechanisms.
Wiener
Zoltan
Z
Division of Immunopathology, Institute of Pathology, University of Berne, Berne, Switzerland.
Ontsouka
Edgar C
EC
Jakob
Sabine
S
Torgler
Ralph
R
Falus
Andras
A
Mueller
Christoph
C
Brunner
Thomas
T
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D053222:Fas Ligand Protein; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005809:Genes, Regulator / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010703:Phorbol Esters / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D019139:Tumor Escape / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C499330:MAX protein, human; C489427:MYC protein, human; D008562:Membrane Glycoproteins; C067850:Myc associated factor X; D016328:NF-kappa B; D010703:Phorbol Esters; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D004317:Doxorubicin