Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calnexin, a chaperone that resides in the endoplasmic reticulum, participates in the quality control function of this compartment. Many glycoproteins in the process of folding associate transiently with this chaperone via interactions involving the recognition of their mono-glucosylated glycans. Some misfolded proteins which are retained in the endoplasmic reticulum exhibit prolonged association with calnexin. We have examined whether the transmembrane and cytoplasmic domains of calnexin influence the association of this chaperone with its targets. Interactions of wild type and truncated calnexin with a glycoprotein that is retained in the endoplasmic reticulum (the lymphocyte tyrosine kinase, Ltk), with membrane IgM heavy chains, and with the MHC class I heavy chain protein were investigated. A soluble calnexin molecule lacking the transmembrane domain and cytoplasmic tail does not associate with any of these proteins. When a heterologous transmembrane domain is fused to the lumenal portion of calnexin, this membrane-bound protein can bind Ltk, IgM heavy chains, and MHC class I heavy chain proteins. These results suggest that calnexin must be membrane-anchored in order to recognize its substrates.
Mol Immunol 1999 Jan
PMID:Membrane anchoring of calnexin facilitates its interaction with its targets. 1036 15

Transcriptional regulation of the MHC class I genes leading to their developmental and tissue specific expression is still poorly understood in spite of the recovery of a large variety of cis-controlling sequences and trans-acting factors pertaining to the 5' enhancer and the downstream regulatory element. Here we produced a series transgenic lines of mice with a genomic subclone of the H2-Kb gene consisting of 367 bp of the 5' upstream region, the coding region and 1.5 kb of the 3' downstream region and carrying all hitherto known regulatory sequences. The comparison of nine transgenic lines carrying the same H2-Kb transgene made it possible to ask whether the cis-information present in the transgene was sufficient for the tissue- and developmental-specific expression and its copy number dependence. We found the proper developmental onset of expression of the transgene at day 13 p.c. and correct tissue specific mRNA levels in adult mice. While in lymphoid tissues and in lung the number of transgene copies still correlated with RNA levels, the copy number dependence was completely lost in liver, kidney and embryonic tissues. Comparison with previously published H2-Kb transgenes indicates that the H2-Kb locus-controlling region is composed of more than one element.
Mol Immunol 1999 Jan
PMID:Lymphoid specificity of a copy number-related expression of the H2-Kb transgene. 1036 22

The classical pathway for MHC class-I-restricted Ag presentation processes cytosolic Ag synthesized in or delivered into the cytosol for binding to MHC class I molecules in the ER. Alternatively, Ag may be processed and bind class I molecules in endocytic compartments or at the cell surface after regurgitation of processed peptides. We show that a 69-mer synthetic polypeptide that carries the optimal 9-mer Kd-restricted epitope from the Plasmodium berghei circumsporozoite protein, PbCS 245-253, is presented to CD8+ T cells after a short incubation (1-2 h) with target cells. The presentation kinetics correlate with the length of the peptides when shorter peptide analogues are used. This presentation is independent of the transporters associated with antigen processing and presentation (TAP), does not require newly synthesized proteins and does not proceed via regurgitation of intracellularly processed peptides. In contrast, it is substantially decreased in the absence of beta2 microglobulin or serum. Taken together, these data suggest that serum components, such as proteases and beta2 microglobulin, allow the processing and loading of exogenous polypeptides onto empty cell surface class I molecules for presentation to CTL.
Mol Immunol 1999 Feb
PMID:Extracellular processing and presentation of a 69-mer synthetic polypetide to MHC class I-restricted T cells. 1037 82

Vaccines are not universal in their ability to induce favorable immune responses in all individuals because the major histocompatibility complex (MHC) molecules needed for presentation of vaccine components to T cells are limited in the peptides they recognize and bind. A heterogeneous cocktail of related peptides synthesized simultaneously and representing amino acids 414-434 of the SIV envelope protein was used to induce immune responses stronger than those induced by a single T cell peptide synthesized conventionally and representing the same region of the viral envelope. The heterogeneous peptide mixture called a hypervariable epitope construct (HEC) was capable of overcoming MHC restriction in peptide presentation in four different inbred mouse strains, including a strain that was a poor responder to the AA 414-434 single sequence peptide (SSP). HEC induced proliferation responses 15 times better than those induced by SSP. Antibodies elicited by HEC but not SSP immunization effectively bind viral antigen. The 414-434 HEC and the 414-434 SSP were also tested for their ability to upregulate the expression of MHC class I molecules on the surface of the mutant RMA-S murine cell line. Surface display of MHC molecules was measured by confocal microscopy followed by calculation of fluorescence intensity of images. HECs upregulated expression of MHC molecules 30% more than SSP peptides. Our findings suggest that HEC cocktails could be effective components of subunit vaccines to help overcome the unresponsiveness observed in outbred animals and in humans as a result of MHC-restricted antigen presentation.
Mol Immunol 1999 Jul
PMID:Hypervariable epitope construct: a synthetic immunogen that overcomes MHC restriction of antigen presentation. 1050 14

The adoptive transfer of tumor-infiltrating lymphocytes along with interleukin 2 into autologous patients resulted in the objective regression of tumor in about 30% of patients with melanoma, indicating that these T cells play a role in tumor rejection. To understand the molecular basis of the T cell-cancer cell interaction we and others started to search for tumor antigens expressed on cancer cells recognized by T cells. This led to the identification of several major histocompatibility complex (MHC) class I restricted tumor antigens. These tumor antigens have been classified into several categories: tissue-specific differentiation antigens, tumor-specific shared antigens, and tumor-specific unique antigens. Because CD4+ T cells play a central role in orchestrating the host immune response against cancer, infectious diseases, and autoimmune diseases, a novel genetic approach has recently been developed to identify these MHC class II restricted tumor antigens. The identification of both MHC class I and II restricted tumor antigens provides new opportunities for the development of therapeutic strategies against cancer. This review summarizes the current status of tumor antigens and their potential applications to cancer treatment.
J Mol Med (Berl) 1999 Sep
PMID:Human tumor antigens: implications for cancer vaccine development. 1056 2

The transporter associated with antigen processing (TAP) plays a key role in the class I major histocompatibility complex (MHC) mediated immune surveillance. It translocates peptides generated by the proteasome complex into the endoplasmic reticulum (ER) for loading onto MHC class I molecules. At the cell surface these MHC complexes are monitored for their antigenic cargo by cytotoxic T-lymphocytes. Peptide binding to TAP is the essential step for peptide selection and for subsequent ATP-dependent translocation into the ER lumen. To examine the pathway of substrate recognition by TAP, we employed peptide epitopes, which were labeled with an environmentally sensitive fluorophore. Upon binding to TAP, a drastic fluorescence quenching of the fluorescent substrate was detected. This allowed us to analyze TAP function in real-time by using a homogeneous assay. Formation of the peptide-TAP complex is composed of a fast association step followed by a slow isomerization of the transport complex. Proton donor groups moving in proximity to the fluorescence label cause fluorescence quenching. Taken together, this peptide-induced structural reorganization may reflect the crosstalk of structural information between the peptide binding site and both nucleotide-binding domains within the TAP complex.
J Mol Biol 1999 Dec 17
PMID:Kinetic analysis of peptide binding to the TAP transport complex: evidence for structural rearrangements induced by substrate binding. 1060 Mar 78

In response to TSH, thyroid cells decrease major histocompatibility (MHC) class I expression and transcription, providing an excellent model for studying the dynamic modulation of transcription of MHC class I genes. Here we show that protein kinase A (PKA), a downstream effector of the TSH/cAMP pathway, reproduces the effects of TSH in repressing class I transcription. PKA/cAMP-mediated repression of transcription involves multiple interacting upstream response elements in the class I promoter: an element extending from -127 to -90 bp containing a CRE-like core, and at least two elements within an upstream 30-bp segment (-160 to -130 bp), which overlaps with the interferon regulatory element. ICER (inducible cAMP early response), a transcriptional repressor induced by TSH/cAMP can decrease class I promoter activity when introduced into FRTL-5 thyroid cells in the absence of TSH/cAMP. ICER binds to both the CRE-like element and the upstream 30-bp segment, generating a novel TSH-induced ternary complex. The present studies led to the proposal that TSH-mediated repression of class I transcription is the result of integrating signals from transcription factors through the higher order interactions of multiple regulatory elements.
Mol Endocrinol 2000 Jan
PMID:Major histocompatibility class I gene transcription in thyrocytes: a series of interacting regulatory DNA sequence elements mediate thyrotropin/cyclic adenosine 3',5'-monophosphate repression. 1062 49

Proteasomal cleavage of proteins is the first step in the processing of most antigenic peptides that are presented to cytotoxic T cells. Still, its specificity and mechanism are not fully understood. To identify preferred sequence signals that are used for generation of antigenic peptides by the proteasome, we performed a rigorous analysis of the residues at the termini and flanking regions of naturally processed peptides eluted from MHC class I molecules. Our results show that both the C terminus (position P1 of the cleavage site) and its immediate flanking position (P1') possess significant signals. The N termini of the peptides show these signals only weakly, consistent with previous findings that antigenic peptides may be cleaved by the proteasome with N-terminal extensions. Nevertheless, we succeed to demonstrate indirectly that the N-terminal cleavage sites contain the same preferred signals at position P1'. This reinforces previous findings regarding the role of the P1' position of a cleavage site in determining the cleavage specificity, in addition to the well-known contribution of position P1. Our results apply to the generation of antigenic peptides and bare direct implications for the mechanism of proteasomal cleavage. We propose a model for proteasomal cleavage mechanism by which both ends of cleaved fragments are determined by the same cleavage signals, involving preferred residues at both P1 and P1' positions of a cleavage site. The compatibility of this model with experimental data on protein degradation products and generation of antigenic peptides is demonstrated.
J Mol Biol 2000 Jan 28
PMID:Sequence signals for generation of antigenic peptides by the proteasome: implications for proteasomal cleavage mechanism. 1065 97

T-cell receptor (TCR) internalization occurs via TCR recognition of the peptide/MHC molecule complex on antigen presenting cell (APC). In this study, the requirements for inducing the internalization of TCR molecules on Ld major histocompatibility complex (MHC) class I-restricted T-cells were investigated with 2C cytotoxic T-lymphocyte (CTL) clones with defined peptides as the antigen. To evaluate the function of the transmembrane region of TCR alphabeta chains in TCR internalization, we generated T-cell transfectants expressing the wild type and glycosylphosphatidyl inositol (GPI)-linked form of 2C TCR. Among all peptides forming proper ligands to 2C TCR, only the Qp2Ca peptide induced TCR internalization, which was known to have the highest affinity to both Ld MHC class I molecules and TCR in association with Ld molecules. Such TCR internalization was not observed in cells expressing the GPI-linked form of 2C TCR. Furthermore, the expression of CD8 coreceptor and Thy-1 accessory molecules were both not required for Qp2Ca-induced TCR internalization, and these molecules did not accompany TCR internalization. Altogether, these results suggest that TCR internalization on CTL is not a prerequisite for CTL function.
Mol Cells 1999 Dec 31
PMID:TCR internalization induced by peptide/MHC ligands requires the transmembrane domains of alphabeta chains of TCR, but not the expression of CD8 and Thy-1 molecules. 1067 28

Tumor immunotherapy is currently receiving close scrutiny. However, with the identification of tumor antigens and their production by recombinant means, the use of cytokines and knowledge of major histocompatibility complex (MHC) class I and class II presentation has provided ample reagents for use and clear indications of how they should be used. At this time, much attention is focused on using peptides to be presented by MHC class I molecules to both induce and be targets for CD8+ cytolytic T cells. Many peptides generated endogenously or given exogenously can enter the class I pathway, but a number of other methods of entering this pathway are also known and are discussed in detail herein. While the review concentrates on inducing cytotoxic T cells (CTLs), it is becoming increasingly apparent that other modes of immunotherapy would be desirable, such as class II presentation to induce increased helper activity (for CTL), but also activating macrophages to be effective against tumor cells.
Cell Mol Life Sci 2000 Feb
PMID:Generation of cellular immune responses to antigenic tumor peptides. 1076 24


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