PubMed · 8640213
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T Elliott. 1996. Tapping into tumours.. https://doi.org/10.1038/ng0696-139
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The transporter 2, ATP-binding cassette, subfamily B (TAP2) is involved in the transport of antigenic peptides to HLA molecules. Coding TAP2 polymorphisms shows a strong association with type 1 diabetes, but it is not clear whether this association may be entirely due to linkage disequilibrium with HLA DR and DQ. Functionally, rat Tap2 nonsynonymous single-nucleotide polymorphisms (nsSNPs) confer differential selectivity for antigenic peptides, but this was not shown to be the case for human TAP2 nsSNPs. In the human, differential peptide selectivity is rather conferred by two splicing isoforms with alternative carboxy terminals. Here, we tested the hypothesis that alleles at the coding SNPs favor different splicing isoforms, thus determining peptide selectivity indirectly. This may be the basis for independent contribution to the type 1 diabetes association. In RNA from heterozygous lymphoblastoid lines, we measured the relative abundance of each SNP haplotype in each isoform. In isoform NM_000544, the G (Ala) allele at 665 Thr>Ala (rs241447) is more than twice as abundant as A (Thr) (GA = 2.2 +/- 0.4, P = 1.5 x 10(-4)), while isoform NM_018833 is derived almost exclusively from chromosomes carrying A (AG = 18.1 +/- 5.6, P = 2.04 x 10(-7)). In 889 Canadian children with type 1 diabetes, differential transmission of parental TAP2 alleles persisted (P = 0.011) when analysis was confined to chromosomes carrying only DQ*02 alleles, which mark a conserved DR-DQ haplotype, thus eliminating most of the variation at DR-DQ. Thus, we present evidence of TAP2 association with type 1 diabetes that is independent of HLA DR-DQ and describe a plausible functional mechanism based on allele dependence of splicing into isoforms known to have differential peptide selectivities.
The eukaryotic GINS complex has an essential role in the initiation and elongation phases of genome duplication. It is composed of four paralogous subunits--Sld5, Psf1, Psf2 and Psf3--which are ubiquitous and evolutionarily conserved in eukaryotic organisms. Here, we report the biochemical characterization of the human GINS complex (hGINS). The four hGINS subunits were coexpressed in Escherichia coli in a highly soluble form and purified as a complex. hGINS was shown to interact directly with the heterodimeric human DNA primase, by using either surface plasmon resonance measurements or by immunoprecipitation experiments carried out with anti-hGINS antibodies. The DNA polymerase alpha-primase synthetic activity was specifically stimulated by hGINS on various primed DNA templates. The significance of these findings is discussed in view of the molecular dynamics at the human replication fork.
Despite continued progress in understanding the pathophysiology of tumours, curative therapeutic options are still lacking for the metastatic form of the disease. One approach that has gathered considerable interest is the creation of therapeutic vaccines using genetically engineered non-replicating viruses as vehicles to revive immunosurveillance mechanisms that may eradicate residual tumour cells. A perceived problem with this approach is that the number of non-replicating viruses used as a vaccine inoculum does not remotely approximate the total number of cells in the body, nor even the number of tumour cells in the case of large tumour burden or metastasis. Here, we addressed the hypothesis that a limited amount of inoculum (1x10(8) PFU) of recombinant non-replicating adenovirus encoding human TAP1 (AdhTAP1) can induce protective immunity against 1.5x10(5) TAP-deficient, metastatic melanoma cells transplanted into a normal mouse (total of approximately 1x10(11) body cells). We show that efficacious anti-tumour cytolytic T cell responses are indeed induced by injecting melanoma-bearing animals with small numbers of recombinant viruses, resulting in increases in tumour-infiltrating dendritic cells, enhanced memory T cell subpopulations and, most importantly, in increased animal survival. This novel approach uses a limited input inoculum relative to the tumour cell mass, and thus achieves an efficacious outcome that has so far eluded other vaccine, immunotherapeutic or gene therapeutic strategies where there is a requisite for the majority of tumour cells to be transduced for beneficial outcome to be achieved.