The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1998/9/1017/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 6, September 21, 1998 1017-1028

Articles

The Sequence Alteration Associated with a Mutational Hotspot in p53 Protects Cells From Lysis by Cytotoxic T Lymphocytes Specific for a Flanking Peptide Epitope

Matthias Theobald*, Thomas Ruppert{ddagger}, Ulrike Kuckelkorn§, Javier Hernandez||, Annett Häussler*, Edite Antunes Ferreira*, Ulrike Liewer*, Judith Biggs||, Arnold J. Levine, Christoph Huber*, Ulrich H. Koszinowski{ddagger}, Peter-M. Kloetzel§, and Linda A. Sherman||

From the * Department of Hematology, Johannes Gutenberg-University, D-55101 Mainz, Germany; the {ddagger} Max von Pettenkofer-Institute for Virology, Ludwig Maximilians University, D-80336 Munich, Germany; the § Institute for Biochemistry, Medical Faculty (Charite), Humboldt University, D-10117 Berlin, Germany, the || Department of Immunology, The Scripps Research Institute, La Jolla, California 92037; and the Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544

A high proportion of tumors arise due to mutation of the p53 tumor suppressor protein. A p53 hotspot mutation at amino acid position 273 from R to H, flanking a peptide epitope that spans residues 264–272, renders cells resistant to killing by human histocompatibility leukocyte antigen (HLA)-A*0201–restricted cytotoxic T lymphocytes (CTLs) specific for this epitope. Acquisition of the R to H mutation at residue 273 of the human p53 protein promotes tumor growth in vivo by selective escape from recognition by p53.264–272 peptide-specific CTLs. Synthetic 27-mer p53 polypeptides covering the antigenic nonamer region 264–272 of p53 were used as proteasome substrates to investigate whether the R to H mutation at the P1' position of the COOH terminus of the epitope affects proteasome-mediated processing of the protein. Analysis of the generated products by tandem mass spectrometry and the kinetics of polypeptide processing in conjunction with CTL assays demonstrate that the R to H mutation alters proteasomal processing of the p53 protein by inhibiting proteolytic cleavage between residues 272 and 273. This prevents the release of the natural CTL epitope that spans flanking residues 264–272 as well as a putative precursor peptide. These results demonstrate that mutation of p53 not only leads to malignant transformation but may also, in some instances, affect immune surveillance and should be considered in the design of cancer vaccines.

Key Words: p53 • tumor antigens • cytotoxic T lymphocytes • antigen processing • proteasomes

Address correspondence to Linda A. Sherman, The Scripps Research Institute, Department of Immunology, IMM-15, 10666 North Torrey Pines Rd., La Jolla, CA 92037. Phone: 619-784-8052; Fax: 619-784-8298; E-mail: lsherman{at}scripps.edu

Abbreviations used: A*0201, HLA-A*0201; β2m, β2 microglobulin; ER, endoplasmic reticulum; Hu, human; MS, mass spectrometry; MS/MS, tandem mass spectrometry; m/z, mass/charge; RP, reversed phase; rVV, recombinant vaccinia virus; Tg, transgenic; WT, wild type.


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