IFN-gamma-mediated coordinated transcriptional regulation of the human TAP-1 and LMP-2 genes in human renal cell carcinoma.
Some human tumor cells exhibit deficient expression of the peptide transporters TAP1 and TAP2 and of the proteasome subunits low molecular weight protein (LMP)-2 and LMP-7, which could be partially restored by cytokine treatment. Here, we show that IFN-gamma stimulation of human renal cell carcinoma lines increased the MHC class I, transporter associated with antigen processing (TAP), and LMP transcript and protein levels, but TAP and LMP expression are more rapidly induced by IFN-gamma than MHC class I molecules. No correlation between the level of induction of the MHC class I antigen presentation genes and IFN sensitivity/resistance was detected. The IFN-gamma-mediated increase of MHC class I, TAP-1, and LMP-2 expression was independent of de novo protein synthesis. Analysis of the dual TAP-1/LMP-2 promoter activity revealed that TAP-1 and LMP-2 expression are controlled by IFN-gamma at the transcriptional level. Site-specific mutations in the IFN-gamma-responsive element of the TAP-1/LMP-2 promoter blocked induction by IFN-gamma. Thus, the IFN-gamma-mediated coordinated transcriptional up-regulation of TAP-1 and LMP-2 expression occurs through the use of a common regulatory element, which might result in enhanced recognition of renal cell carcinoma cells by the immune system.
Seliger
B
B
III. Medical Clinic, Department of Hematology/Oncology, Johannes Gutenberg-University, 55101 Mainz, Germany.
Hammers
S
S
Höhne
A
A
Zeidler
R
R
Knuth
A
A
Gerharz
C D
CD
Huber
C
C
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000276:immunology; D003546:Cysteine Endopeptidases; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000276:immunology; D007700:Kinetics; D008285:Major Histocompatibility Complex; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D011506:Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C073119:TAP1 protein, human; C071313:LMP-2 protein; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases