RRC ID 10811
Author Hayashi T, Kobayashi Y, Kohsaka S, Sano K.
Title The mutation in the ATP-binding region of JAK1, identified in human uterine leiomyosarcomas, results in defective interferon-gamma inducibility of TAP1 and LMP2.
Journal Oncogene
Abstract The presentation of human leukocyte antigens (HLA) class I requires the coordinated expression of numerous components involved in antigen presentation. Tumor cells may alter the antigen presentation by HLA class I, allowing them to evade antitumor immunity. In many cases, the lack of antigen presentation can be attributed to the downregulation of genes needed for antigen processing, such as the transporters associated with antigen processing (TAP) 1, and the proteasomal component, low molecular weight proteins (LMP) 2. The TAP1 and LMP2 genes are transcribed from a shared bidirectional promoter containing an interferon (IFN)-gamma-response factor element; thus, the IFN-gamma-signal strongly induces both TAP1 and LMP2 expression. Low molecular weight proteins2-deficient mice exhibited the development of uterine leiomyosarcomas. Here, the differential responsiveness to IFN-gamma of the SKN human uterine leiomyosarcomas cell line was investigated. We now identify the G871E mutation in the ATP-binding region of Janus kinases 1, suggesting that the loss of TAP1 and LMP2 induction is a defect in the earliest steps of the IFN-gamma-signal pathway, resulting in the inability of SKN cells to upregulate the antigen-processing pathway. Understanding the mechanisms by which these tumors circumvent cytokine signalling, thereby evading antitumor-specific immunity, would greatly aid the efficacy of immunotherapy for treating uterine leiomyosarcomas.
Volume 25(29)
Pages 4016-26
Published 2006-7-6
DOI 10.1038/sj.onc.1209434
PII 1209434
PMID 16474838
MeSH ATP Binding Cassette Transporter, Subfamily B, Member 2 ATP-Binding Cassette Transporters / genetics ATP-Binding Cassette Transporters / immunology Adenosine Triphosphate / genetics Adenosine Triphosphate / immunology Amino Acid Substitution / genetics Amino Acid Substitution / immunology Animals Antigen Presentation / drug effects Antigen Presentation / genetics Antigen Presentation / immunology Antigens, Neoplasm / genetics Antigens, Neoplasm / immunology Cysteine Endopeptidases / genetics Cysteine Endopeptidases / immunology Female Gene Expression Regulation, Neoplastic / drug effects Gene Expression Regulation, Neoplastic / genetics Gene Expression Regulation, Neoplastic / immunology Genes, MHC Class I / immunology HeLa Cells Humans Immunotherapy Interferon-gamma / immunology Interferon-gamma / pharmacology Janus Kinase 1 Leiomyoma / genetics* Leiomyoma / immunology Leiomyoma / therapy Mice Mice, Knockout Point Mutation* / immunology Protein Binding / genetics Protein Binding / immunology Protein Structure, Tertiary / genetics Protein-Tyrosine Kinases / genetics* Protein-Tyrosine Kinases / immunology Sarcoma / genetics* Sarcoma / immunology Sarcoma / therapy Signal Transduction / genetics Signal Transduction / immunology Tumor Escape / drug effects Tumor Escape / genetics* Tumor Escape / immunology Uterine Neoplasms / genetics* Uterine Neoplasms / immunology Uterine Neoplasms / therapy
IF 6.854
Times Cited 19
Human and Animal Cells SKN (RCB0513)