Assessment of tumor necrosis factor receptor and Fas signaling pathways by transcriptional profiling.
Apoptosis, or programmed cell death, is an important mechanism by which cells are eliminated during immune regulation and embryonic development. Aberrations in the signaling pathways leading to apoptosis may result in cancer, autoimmune diseases, or inflammatory disorders. In view of this, an understanding of the signaling capabilities of apoptosis-inducing or death receptors is essential to understanding their roles in biology and disease. We used cDNA microarrays to examine the downstream transcriptional effects of two members of the tumor necrosis factor (TNF) family of death receptor ligands. We compared the transcriptional responses of a model colon cancer cell line, HT29, to TNF-alpha and anti-Fas activating antibody. Both ligands induced a subset of genes characteristic of activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Follow-up analyses demonstrated that, although TNF-alpha activated NF-kappaB through IkappaB-alpha degradation, alpha-Fas treatment led to NF-kappaB activation through a mechanism distinct from IkappaB-alpha degradation.
Manos
E J
EJ
Division of Molecular Pharmacology, Huntsman Cancer Institute, University of Utah, Salt Lake City 84112, USA.
Jones
D A
DA
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins; D007371:Interferon-gamma / Q000494:pharmacology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma