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Gene Review

Trpc4ap  -  transient receptor potential cation...

Mus musculus

Synonyms: 4833429F06Rik, D2Ertd113e, Protein TAP1, Protein TRUSS, Rabex-5/Rin2-interacting protein, ...
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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


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


Regulatory relationships of Trpc4ap


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


  1. TAP expression provides a general method for improving the recognition of malignant cells in vivo. Alimonti, J., Zhang, Q.J., Gabathuler, R., Reid, G., Chen, S.S., Jefferies, W.A. Nat. Biotechnol. (2000) [Pubmed]
  2. Identification of mechanisms underlying transporter associated with antigen processing deficiency in metastatic murine carcinomas. Setiadi, A.F., David, M.D., Chen, S.S., Hiscott, J., Jefferies, W.A. Cancer Res. (2005) [Pubmed]
  3. TAP peptide transporter-independent presentation of heat-killed Sendai virus antigen on MHC class I molecules by splenic antigen-presenting cells. Liu, T., Chambers, B., Diehl, A.D., Van Kaer, L., Jondal, M., Ljunggren, H.G. J. Immunol. (1997) [Pubmed]
  4. MHC class I-mediated antigen presentation and induction of CD8+ cytotoxic T-cell responses in autoimmune diabetes-prone NOD mice. Serreze, D.V., Gallichan, W.S., Snider, D.P., Croitoru, K., Rosenthal, K.L., Leiter, E.H., Christianson, G.J., Dudley, M.E., Roopenian, D.C. Diabetes (1996) [Pubmed]
  5. Peptide contributes to the specificity of positive selection of CD8+ T cells in the thymus. Ashton-Rickardt, P.G., Van Kaer, L., Schumacher, T.N., Ploegh, H.L., Tonegawa, S. Cell (1993) [Pubmed]
  6. TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective. Shepherd, J.C., Schumacher, T.N., Ashton-Rickardt, P.G., Imaeda, S., Ploegh, H.L., Janeway, C.A., Tonegawa, S. Cell (1993) [Pubmed]
  7. TAP1 mutant mice are deficient in antigen presentation, surface class I molecules, and CD4-8+ T cells. Van Kaer, L., Ashton-Rickardt, P.G., Ploegh, H.L., Tonegawa, S. Cell (1992) [Pubmed]
  8. Proto-oncogene PML controls genes devoted to MHC class I antigen presentation. Zheng, P., Guo, Y., Niu, Q., Levy, D.E., Dyck, J.A., Lu, S., Sheiman, L.A., Liu, Y. Nature (1998) [Pubmed]
  9. The interferon regulatory transcription factor IRF-1 controls positive and negative selection of CD8+ thymocytes. Penninger, J.M., Sirard, C., Mittrücker, H.W., Chidgey, A., Kozieradzki, I., Nghiem, M., Hakem, A., Kimura, T., Timms, E., Boyd, R., Taniguchi, T., Matsuyama, T., Mak, T.W. Immunity (1997) [Pubmed]
  10. MHC class I pathway is not required for the development of crescentic glomerulonephritis in mice. Li, S., Holdsworth, S.R., Tipping, P.G. Clin. Exp. Immunol. (2000) [Pubmed]
  11. TRUSS, a novel tumor necrosis factor receptor 1 scaffolding protein that mediates activation of the transcription factor NF-kappaB. Soond, S.M., Terry, J.L., Colbert, J.D., Riches, D.W. Mol. Cell. Biol. (2003) [Pubmed]
  12. Regulation of LMP2 and TAP1 genes by IRF-1 explains the paucity of CD8+ T cells in IRF-1-/- mice. White, L.C., Wright, K.L., Felix, N.J., Ruffner, H., Reis, L.F., Pine, R., Ting, J.P. Immunity (1996) [Pubmed]
  13. Comparison of cell lines deficient in antigen presentation reveals a functional role for TAP-1 alone in antigen processing. Gabathuler, R., Reid, G., Kolaitis, G., Driscoll, J., Jefferies, W.A. J. Exp. Med. (1994) [Pubmed]
  14. Downregulation of peptide transporter genes in cell lines transformed with the highly oncogenic adenovirus 12. Rotem-Yehudar, R., Winograd, S., Sela, S., Coligan, J.E., Ehrlich, R. J. Exp. Med. (1994) [Pubmed]
  15. The basis for self-tolerance of natural killer cells in beta2-microglobulin- and TAP-1- mice. Dorfman, J.R., Zerrahn, J., Coles, M.C., Raulet, D.H. J. Immunol. (1997) [Pubmed]
  16. Heat-inactivated Sendai virus can enter multiple MHC class I processing pathways and generate cytotoxic T lymphocyte responses in vivo. Liu, T., Zhou, X., Orvell, C., Lederer, E., Ljunggren, H.G., Jondal, M. J. Immunol. (1995) [Pubmed]
  17. MHC class I-restricted presentation of maleylated protein binding to scavenger receptors. Bansal, P., Mukherjee, P., Basu, S.K., George, A., Bal, V., Rath, S. J. Immunol. (1999) [Pubmed]
  18. Major histocompatibility complex class I presentation of ovalbumin peptide 257-264 from exogenous sources: protein context influences the degree of TAP-independent presentation. Wick, M.J., Pfeifer, J.D. Eur. J. Immunol. (1996) [Pubmed]
  19. Nucleotide binding of the C-terminal domains of the major histocompatibility complex-encoded transporter expressed in Drosophila melanogaster cells. Wang, K., Früh, K., Peterson, P.A., Yang, Y. FEBS Lett. (1994) [Pubmed]
  20. Effect of interleukin-2 on generation of natural killer cells: role of major histocompatibility complex class I in B6 and TAP-1-/- mice. Delfino, D.V., Di Marco, B., Marchetti, C., Bartoli, A., Ayroldi, E., Bruscoli, S., Agostini, M., Spinicelli, S., Zollo, O., Migliorati, G. Journal of chemotherapy (Florence, Italy) (2000) [Pubmed]
  21. MHC class I expression in murine skin: developmentally controlled and strikingly restricted intraepithelial expression during hair follicle morphogenesis and cycling, and response to cytokine treatment in vivo. Rückert, R., Hofmann, U., van der Veen, C., Bulfone-Paus, S., Paus, R. J. Invest. Dermatol. (1998) [Pubmed]
  22. Regulation of major histocompatibility complex and TAP gene products in preimplantation mouse stage embryos. Cooper, J.C., Fernandez, N., Joly, E., Dealtry, G.B. Am. J. Reprod. Immunol. (1998) [Pubmed]
  23. MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components. Garcia-Lora, A., Martinez, M., Algarra, I., Gaforio, J.J., Garrido, F. Int. J. Cancer (2003) [Pubmed]
  24. Resistance to lysis by cytotoxic T cells: a dominant effect in metastatic mouse prostate cancer cells. Lee, H.M., Timme, T.L., Thompson, T.C. Cancer Res. (2000) [Pubmed]
  25. Constitutive IL-10 production accounts for the high NK sensitivity, low MHC class I expression, and poor transporter associated with antigen processing (TAP)-1/2 function in the prototype NK target YAC-1. Petersson, M., Charo, J., Salazar-Onfray, F., Noffz, G., Mohaupt, M., Qin, Z., Klein, G., Blankenstein, T., Kiessling, R. J. Immunol. (1998) [Pubmed]
  26. Transporters from H-2b, H-2d, H-2s, H-2k, and H-2g7 (NOD/Lt) haplotype translocate similar sets of peptides. Schumacher, T.N., Kantesaria, D.V., Serreze, D.V., Roopenian, D.C., Ploegh, H.L. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  27. Mapping of quantitative trait Loci determining NK cell-mediated resistance to MHC class I-deficient bone marrow grafts in perforin-deficient mice. Johansson, M.H., Taylor, M.A., Jagodic, M., Tus, K., Schatzle, J.D., Wakeland, E.K., Bennett, M. J. Immunol. (2006) [Pubmed]
  28. The role of CD8(+) T cells and major histocompatibility complex class I expression in the central nervous system of mice infected with neurovirulent Sindbis virus. Kimura, T., Griffin, D.E. J. Virol. (2000) [Pubmed]
  29. Involvement of natural killer T cells and granulocytes in the inflammation induced by partial hepatectomy. Kato, T., Sato, Y., Takahashi, S., Kawamura, H., Hatakeyama, K., Abo, T. J. Hepatol. (2004) [Pubmed]
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