Mutated mitogen-activated protein kinase: a tumor rejection antigen of mouse sarcoma.
The molecular basis of the polymorphic tumor rejection antigens of chemically induced sarcomas of inbred mice remains a mystery, despite the discovery of these antigens over 40 years ago and their critical importance to the foundation of tumor immunology. In an analysis of a panel of BALB/c 3-methylcholanthrene-induced tumors, we identified one tumor, CMS5, that elicited a strong cytotoxic T cell response with exquisite specificity for CMS5. A stable cloned line of T cells with this specificity (C18) was used to screen a CMS5 cDNA expression library. The gene encoding the C18-defined antigen was identified as a mutated form of a mouse mitogen-activated protein kinase, ERK2, and a peptide incorporating the resulting amino acid substitution (lysine to glutamine) was efficiently recognized by C18. Vaccination with this peptide elicited specific resistance to CMS5 challenge. Extensive efforts to isolate antigen-loss variants of CMS5 were unsuccessful, suggesting that the mutated mitogen-activated protein kinase is essential for maintenance of the malignant phenotype.
Ikeda
H
H
2nd Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514, Japan.
Ohta
N
N
Furukawa
K
K
Miyazaki
H
H
Wang
L
L
Kuribayashi
K
K
Old
L J
LJ
Shiku
H
H
D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018076:DNA, Complementary; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D019950:Mitogen-Activated Protein Kinase 1; D008969:Molecular Sequence Data; D016296:Mutagenesis; D016297:Mutagenesis, Site-Directed; D009368:Neoplasm Transplantation / Q000276:immunology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D016415:Sequence Alignment; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014185:Transplantation, Isogeneic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018076:DNA, Complementary; D000939:Epitopes; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008748:Methylcholanthrene; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1