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J. Exp. Med.,
Volume 188, Number 6, September 21, 1998 1017-1028
By
From the * Department of Hematology, Johannes Gutenberg-University, D-55101 Mainz, Germany;
the 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.
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
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