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

Content Provider	PubMed Central
Author	Theobald, Matthias Ruppert, Thomas Ulrike, Kuckelkorn Hernandez, Javier Annett, Häussler Ferreira, Edite Antunes Ulrike, Liewer Biggs, Judith Levine, Arnold J. Huber, Christoph Koszinowski, Ulrich H. Kloetzel, Peter-m. Sherman, Linda A.
Copyright Year	1998
Abstract	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.
Starting Page	1017
File Format	PDF
ISSN	15409538
e-ISSN	15409538
Journal	The Journal of Experimental Medicine
Issue Number	6
Volume Number	188
Language	English
Publisher	The Rockefeller University Press
Publisher Date	1998-09-21
Access Restriction	Open
Rights Holder	The Rockefeller University Press
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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