Disease relevance of Trpc4ap

• To test the potential of providing exogenous TAP in cancer therapies, we constructed a vaccinia virus (VV) containing the TAP1 gene and examined whether VV-TAP1 could reduce tumors in mice [1].
• By chromatin immunoprecipitation assay, we showed that the recruitment of RNA polymerase II to the TAP-1 gene was impaired in TAP-deficient cells derived from murine melanoma, prostate, and lung carcinomas, compared with TAP-expressing fibroblasts and lymphoma cells [2].
• Based on these results, we propose that TAP deficiency in many carcinomas is caused by a decrease in activity/expression of trans-acting factors regulating TAP-1 promoter activity, as well as a decrease in TAP-1 mRNA stability [2].
• Heat-killed Sendai virus Ags were efficiently processed by normal B6 as well as by TAP-1(-/-) splenic APC [3].
• One laboratory has reported that the peptide transporter encoded by the Tap1 gene within H2g7 is defective, and this contributes to IDDM by impairing MHC class I-mediated antigen presentation [4].

High impact information on Trpc4ap

• Mice deficient in the gene encoding the peptide transporter associated with antigen processing (TAP1) have drastically reduced levels of surface expression of MHC class I molecules and few CD8+ T cells [5].
• In this study, we demonstrate in a cell-free system that TAP1 is part of an ATP-dependent, sequence-specific, peptide translocator [6].
• We have generated mice with a disrupted TAP1 gene using embryonic stem cell technology [7].
• Here we report that the proto-oncogene product PML induces expression of LMP-2, LMP-7, TAP-1 and TAP-2 in an MHC-class I-negative, recurrent tumour, leading to the re-expression of cell-surface MHC in tumours and to rejection of the tumours [8].
• The absence of IRF-1 resulted in decreased expression of LMP2, TAP1, and MHC class I on thymic stromal cells [9].

Chemical compound and disease context of Trpc4ap

• Heterozygous TAP-1 mice have normal MHC I expression and developed GN with crescents in 42 +/- 4% of glomeruli (normal 0%), proteinuria (9.1 +/- 1.6 mg/20 h, normal 1.5 +/- 0.3 mg/20 h) and impaired renal function (creatinine clearance 110 +/- 8 microl/min, normal 193 +/- 10 microl/min) following administration of sheep anti-mouse GBM globulin [10].

Biological context of Trpc4ap

• Deletion mutagenesis of TNF-R1 indicated that TRUSS interacts with both the membrane-proximal region and the death domain of TNF-R1 [11].
• The transporter associated with the antigen processing 1 (TAP1) gene encodes a subunit for a transporter, presumed to be involved in the delivery of peptides across the endoplasmic reticulum membrane to class I molecules [7].
• Here, we analyze the molecular mechanism of IFN gamma up-regulation of TAP1 and LMP2 [12].
• These results indicate that a TAP-1 homodimer may translocate peptides in the ER and explain partially the CMT.64 defect and the RMA-S phenotype [13].
• Reconstitution of PD1 and H-2Db, but not H-2Kb, expression is achieved in an Ad12-transformed cell line by stable transfection with a TAP2, but not a TAP1, expression construct [14].

Anatomical context of Trpc4ap

• TRUSS mRNA was ubiquitously expressed in mouse tissues but was enriched in heart, liver, and testis [11].
• As predicted from the near absence of class I surface expression, TAP1-deficient mice lack CD4-8+ T cells [7].
• Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing [13].
• However, these fused cells exhibited lower levels of TAP-1 mRNA and H-2k than unfused fibroblasts [2].
• Although NK cells are present in beta2m- mice and TAP-1(-) mice, they are completely self-tolerant [15].

Associations of Trpc4ap with chemical compounds

• In T1Kb- and TAP1/2-transfected T2Kb cells, as in T2Kb cells, processing of heat-inactivated SV was completely BFA resistant [16].
• Presentation was MHC class I restricted, since no presentation was seen by APC from TAP-1/beta2m-/- mice that lack expression of MHC class I. Presentation occurred even in the presence of brefeldin A, but was blocked by cytochalasin D as well as chloroquine [3].
• This enhanced presentation involved uptake through receptors of scavenger receptor (SR)-like ligand specificity, was TAP-1-independent, and was inhibited by low levels (2 mM) of ammonium chloride [17].
• TAP1-/- or C57BL/6 macrophages were co-incubated with either bacteria or polystyrene beads containing the 257-264 epitope from ovalbumin [OVA(257-264)], which binds the mouse class I molecule Kb [18].
• The relative potencies of the nucleotides in preventing azido-ATP labeling were in the order of ATP > GTP > CTP > ITP > UTP for both the TAP1 and TAP2 C-terminal domains, suggesting ATP to be the natural substrate of the transporter [19].

Physical interactions of Trpc4ap

• Effect of interleukin-2 on generation of natural killer cells: role of major histocompatibility complex class I in B6 and TAP-1-/- mice [20].

Regulatory relationships of Trpc4ap

• H2b, Qa-1, and TAP-1 immunoreactivity on previously negative keratinocytes of the proximal anagen hair bulb was upregulated by intradermal injection of the proinflammatory cytokine interferon-gamma, but not by tumor necrosis factor-alpha or interleukin-1beta [21].

Other interactions of Trpc4ap

• H-2 class Ia (classical) protein was detected on the surface of two-cell embryos, H-2 class Ib (nonclassical) protein was detected on one-cell embryos, and beta 2-m transcripts were detected on eight-cell embryos; TAP1 protein was present at low levels in the cytoplasm from the one-cell stage onward, increasing in expression in blastocysts [22].
• Analyses with RT-PCR showed that TAP-1, TAP2, LMP-2, LMP7, LMP10, tapasin and calnexin mRNA specific for these genes was absent in metastases produced in immunocompetent mice [23].
• IFN-gamma induced surface class I MHC expression, as well as gene expression of TAP-1, TAP-2, LMP-2, and LMP-7 in the metastatic cells, yet the cells remained resistant to cell lysis induced by CTLs [24].
• In addition, differences in YAC-1 MHC class I expression correlated with alterations in the functional activity of TAP-1/2 proteins [25].

Analytical, diagnostic and therapeutic context of Trpc4ap

• Co-immunoprecipitation experiments showed that TRUSS was constitutively associated with unligated TNF-R1 and that the complex was relatively insensitive to stimulation with TNF-alpha [11].
• A limited degree of sequence polymorphism has been observed for the mouse TAP1 and TAP2 genes by restriction fragment length polymorphism and sequence analysis [26].
• In transplantation experiments, >350 backcross 1 progeny were analyzed and displayed a great variation in ability to reject TAP-1 KO BM grafts [27].
• On the other hand, in situ hybridization with probes for MHC class I heavy chain, beta2 microglobulin, and TAP1 and TAP2 mRNAs revealed increased expression in a majority of neurons, as well as in inflammatory cells, endothelial cells, and ependymal cells in the central nervous system of infected mice [28].
• In TAP-1(-/-) mice which lacked CD8+ cytotoxic T cells, inflammation remained at a normal level after partial hepatectomy [29].

References