Rate of antigen degradation by the ubiquitin-proteasome pathway influences MHC class I presentation.

Grant, Ethan P.; Michalek, M T; Goldberg, A L; Rock, Kenneth L.

doi:10.4049/jimmunol.155.8.3750

Cited by 130 publications

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Protection against mammary tumor growth by vaccination with full-length, modified humanErbB-2 DNA

et al. 1999

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ErbB‐2 is overexpressed in several human cancers and conveys a transforming activity that is dependent on tyrosine kinase activity. Antibodies and T cells to ErbB‐2 have been isolated from cancer patients, indicating ErbB‐2 as a potential target of active vaccination. In this study, 3 mutant ErbB‐2 DNA constructs encoding full‐length, ErbB‐2 proteins were tested as tumor vaccines. To eliminate tyrosine kinase activity, the ATP binding lysine residue 753 was substituted with alanine by replacing codon AAA with GCA in mutant ErbB‐2A. To direct recombinant ErbB‐2 to the cytoplasm where major histocompatibility complex (MHC) I peptide processing takes place, the endoplasmic reticulum (ER) signal sequence was deleted in cyt ErbB‐2. The third construct cyt ErbB‐2A contained cytoplasmic ErbB‐2 with the K to A mutation. Expression of recombinant proteins was measured by flow cytometry in transfected murine mammary tumor cell line D2F2. Transmembrane ErbB‐2 and ErbB‐2A were readily detected. Cytoplasmic ErbB‐2 and ErbB‐2A were detected only after the transfected cells were incubated overnight with a proteasome inhibitor, indicating prompt degradation upon synthesis. ErbB‐2 autophosphorylation was eliminated by the K to A mutation as demonstrated by Western blot analysis. Growth of ErbB‐2‐positive tumor in BALB/c mice was inhibited after vaccination with ErbB‐2 or ErbB‐2A, but not with cyt ErbB‐2 or cyt ErbB‐2A. ErbB‐2A that is free of tyrosine kinase activity is a potential candidate for anticancer vaccination. The 3 mutant constructs should be useful tools to delineate the role of individual immune effector cell in ErbB‐2‐specific antitumor immunity and to develop strategies for enhancing such immunity. Int. J. Cancer 81:748–754, 1999. © 1999 Wiley‐Liss, Inc.

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Protection against mammary tumor growth by vaccination with full-length, modified humanErbB-2 DNA

et al. 1999

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Identification and analysis of a novel member of the ubiquitin family expressed in dendritic cells and mature B cells

Bates¹,

Ravel²,

Dieu³

et al. 1997

Eur J Immunol

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Using a cDNA subtraction technique, a novel member of the ubiquitin family was isolated from human dendritic cells. This gene encodes a diubiquitin protein containing tandem head to tail ubiquitin-like domains, with the conservation of key functional residues. Expression of this 777-bp mRNA was restricted to dendritic cells and B cells, with strong expression in mature B cells. Southern blot analysis indicated that a single copy of this gene is present. In situ hybridization on tonsillar tissue showed expression in epithelial cells and isolated cells within the germinal center. With respect to an expressed-sequence tag (EST) this cDNA could be localized to the major histocompatibility complex class I region of chromosome 6. Comparative analysis and the expression pattern of this gene suggests a function in antigen processing and presentation.

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Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome

Kim

Grum-Tokars

Swanson

et al. 2003

J of Neuroscience Research

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Neuropeptide processing metalloenzymes, such as angiotensin converting enzyme, neprilysin, endothelin converting enzyme, neurolysin, and EC3.4.24.15 (EP24.15), are central to the formation and degradation of bioactive peptides. We present EP24.15 as a paradigm for novel functions ascribed to these enzymes in the neurome. Although the neurome typically encompasses proteomes of the brain and central nervous system, exciting new roles of these neuropeptidases have been demonstrated in other organ systems. We discuss the involvement of EP24.15 with clinical sequelae involving the use of gonadotropin-releasing hormone (GnRH; LHRH) analogs that act as enzyme inhibitors, in vascular physiology (blood pressure regulation), and in the hematologic system (immune surveillance). Hemodynamic forces, such as cyclic strain and shear stress, on vascular cells, induce an increase in EP24.15 transcription, suggesting that neuropeptidase-mediated hydrolysis of pressor/depressor peptides is likely regulated by changes in hemodynamic force and blood pressure. Lastly, EP24.15 regulates surface expression of major histocompatibility complex Class I proteins in vivo, suggesting that EP24.15 may play an important role in maintenance of immune privilege in sites of increased endogenous expression. In these extraneural systems, regulation of both neuropeptide and other peptide substrates by neuropeptidases indicates that the influence of these enzymes may be more global than was anticipated previously, and suggests that their attributed role as neuropeptidases underestimates their physiologic actions in the neural system.

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Rate of antigen degradation by the ubiquitin-proteasome pathway influences MHC class I presentation.

Cited by 130 publications

References 0 publications

Protection against mammary tumor growth by vaccination with full-length, modified humanErbB-2 DNA

Protection against mammary tumor growth by vaccination with full-length, modified humanErbB-2 DNA

Identification and analysis of a novel member of the ubiquitin family expressed in dendritic cells and mature B cells

Novel roles of neuropeptide processing enzymes: EC3.4.24.15 in the neurome

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