A single-nucleotide deletion leads to rapid degradation of TAP-1 mRNA in a melanoma cell line.
Both viruses and tumors evade cytotoxic T lymphocyte-mediated host immunity by down-regulation of antigen presentation machineries. This can be achieved by either down-regulation of transcription of antigen presentation genes or posttranslational inactivation of proteins involved in antigen presentation. In this study, a major histocompatibility complex (MHC) class I-deficient melanoma cell line, SK-MEL-19, was found deficient in the expression of the transporter associated with antigen processing (TAP)-1 mRNA even after IFN-gamma stimulation, despite its active transcription of the TAP-1 gene. This abnormality was caused by a single-nucleotide deletion at position +1489 of the TAP-1 gene and was corrected by cycloheximide, which inhibits RNA degradation. Using an inducible Tet-Off system, we demonstrated that deletion of the nucleotide resulted in a >2-fold decrease in the half-life of TAP-1 mRNA. However, the decrease of the half-life of TAP-1 mRNA is not mediated by nonsense-mediated mRNA decay because deletions of two additional nucleotides in the region, which corrected the nonsense mutation, did not restore TAP-1 mRNA stability. To our knowledge, this is the first evidence that the degradation of mRNA of an antigen presentation gene is involved in HLA class I down-regulation in malignant cells.
Yang
Tianyu
T
Department of Pathology and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.
McNally
Beth A
BA
Ferrone
Soldano
S
Liu
Yang
Y
Zheng
Pan
P
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D017951:Antigen Presentation / Q000235:genetics; D018389:Codon, Nonsense; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D016368:Frameshift Mutation; D015395:Histocompatibility Antigens Class I; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020871:RNA Stability / Q000187:drug effects / Q000235:genetics*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D018389:Codon, Nonsense; D016326:Extracellular Matrix Proteins; D015395:Histocompatibility Antigens Class I; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C073119:TAP1 protein, human; D003513:Cycloheximide